Clinical Focus

  • Cancer > Breast Cancer
  • Triple-negative breast cancer
  • BRCA1 and BRCA2 mutation-associated breast cancer
  • Hereditary breast cancer
  • Metastatic breast cancer
  • Locally advanced breast cancer
  • Medical Oncology

Academic Appointments

Administrative Appointments

  • Program Committee, ASCO Breast Cancer Symposium (2010 - 2013)
  • Scientific Program Committee, Triple Negative Breast Cancer/Cytotoxics/Local Therapy, American Society of Clinical Oncology (2010 - 2013)
  • Breast Cancer Maintenance of Certification Working Group, American Society of Clinical Oncology (2013 - 2014)
  • Breast Cancer Guidelines Panel, National Comprehensive Cancer Network (2014 - Present)
  • Medical Oncology SEP Committee, American Board of Internal Medicine (2014 - Present)
  • Breast Oncology Protocol Review Committee Co-Chair, Stanford University (2015 - Present)
  • Komen Scholar, Susan G. Komen for the Cure (2015 - Present)
  • Scientific Review Committee, Stanford Cancer Institute (2016 - Present)

Honors & Awards

  • Fellowship Award, Susan G. Komen for the Cure (2008)
  • Merit Award, American Society of Clinical Oncology (2008)
  • Young Investigator Award, American Society of Clinical Oncology (2009)
  • Oncology Division Teaching Award, Stanford University School of Medicine (2010, 2012, 2013, 2014)
  • New Investigator Award, Stanford Cancer Institute (2011)
  • Career Catalyst Research Award, Susan G. Komen for the Cure (2012)
  • Champion Award, Triple Step Toward the Cure (2015)
  • Komen Leadership Award, Susan G. Komen for the Cure (2015)
  • Nadia's Gift, Nadia's Gift Foundation (2015)

Professional Education

  • B.A., University of Pennsylvania, Biology, with Distinction (1996)
  • M.D., George Washington University, Medicine, with Distinction (2002)
  • Residency, Stanford University, Internal Medicine (2005)
  • Fellowship, Stanford University, Medical Oncology (2008)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2005)
  • Board Certification: Medical Oncology, American Board of Internal Medicine (2008)
  • Board Certification, American Board of Internal Medicine, Internal Medicine (2015)

Community and International Work

  • Triple Step Toward the Cure, Mill Valley, CA



    Ongoing Project


    Opportunities for Student Involvement


  • Facing Our Risk of Cancer Empowered (FORCE), Tampa, Florida



    Ongoing Project


    Opportunities for Student Involvement


  • Bay Area Cancer Connections, Palo Alto, CA



    Ongoing Project


    Opportunities for Student Involvement


Research & Scholarship

Current Research and Scholarly Interests

My research focuses on breast cancer treatment and survivorship. My primary research interest is the development of novel strategies for the treatment of early stage triple-negative and BRCA1/2 mutation-associated breast cancer. Other areas of interest include prevention of cardiac damage associated with breast cancer treatment and cardiotoxicity of anti-cancer agents.

Clinical Trials

  • A Study Evaluating Safety and Efficacy of the Addition of ABT-888 Plus Carboplatin Versus the Addition of Carboplatin to Standard Chemotherapy Versus Standard Chemotherapy in Subjects With Early Stage Triple Negative Breast Cancer Not Recruiting

    This is a 3 arm Phase 3 study to evaluate the safety and efficacy of the addition of veliparib plus carboplatin versus the addition of carboplatin to standard neoadjuvant chemotherapy versus standard neoadjuvant chemotherapy in subjects with early stage TNBC.

    Stanford is currently not accepting patients for this trial. For more information, please contact Pei Jen Chang, 650-725-0866.

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  • PALbociclib CoLlaborative Adjuvant Study: A Randomized Phase III Trial of Palbociclib With Standard Adjuvant Endocrine Therapy Versus Standard Adjuvant Endocrine Therapy Alone for Hormone Receptor Positive (HR+) / Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Early Breast Cancer Recruiting

    This is a prospective, two arm, international, multicenter, randomized, open-label Phase III study evaluating the addition of 2 years of palbociclib to standard adjuvant endocrine therapy for patients with HR+ / HER2- early breast cancer (EBC). The purpose of the PALLAS study is to determine whether the addition of palbociclib to adjuvant endocrine therapy will improve outcomes over endocrine therapy alone for HR+/HER2- early breast cancer. Assessment of a variety of correlative analysis, including evaluation of the effect of palbociclib in genomically defined tumor subgroups, is planned.

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  • The Study Evaluating Efficacy And Tolerability Of Veliparib in Combination With Temozolomide or In Combination With Carboplatin and Paclitaxel Versus Placebo in Subjects With BRCA1 and BRCA2 Mutation and Metastatic Breast Cancer Not Recruiting

    The Study Evaluating Efficacy And Tolerability of Veliparib in Combination with Temozolomide or Veliparib/Placebo in Combination with Carboplatin and Paclitaxel in Subjects with locally recurrent Breast Cancer not amenable to therapy with curative intent, or metastatic breast cancer and a documented (BRCA1) and (BRCA2) deleterious germline mutation.

    Stanford is currently not accepting patients for this trial. For more information, please contact Pei-Jen Chang, (650) 725 - 0866.

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  • A Phase II Clinical Trial of PM01183 in BRCA 1/2-Associated or Unselected Metastatic Breast Cancer Recruiting

    A Clinical Trial of PM01183 in Metastatic Breast Cancer to assess the antitumor activity of PM01183 ,to evaluate whether the presence of a known germline mutation in BRCA 1/2 predicts response to PM01183 in Metastatic Breast Cancer (MBC) patients, to evaluate the safety profile of this PM01183 to analyze the pharmacokinetics (PK) and PK/PD (pharmacokinetic/pharmacodynamic) correlations and to evaluate the pharmacogenomic (PGx) expression profile in tumor samples.

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  • Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab With or Without Estrogen Deprivation in Treating Patients With Hormone Receptor-Positive, HER2-Positive Operable or Locally Advanced Breast Cancer Not Recruiting

    This randomized phase III trial studies docetaxel, carboplatin, trastuzumab, and pertuzumab with estrogen deprivation to see how they work compared to docetaxel, carboplatin, trastuzumab, and pertuzumab without estrogen deprivation in treating patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer that is operable or has spread from where it started to nearby tissue or lymph nodes (locally advanced). Drugs used in chemotherapy, such as docetaxel, carboplatin, trastuzumab, and pertuzumab, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Estrogen can cause the growth of breast cancer cells. Hormone therapy using goserelin acetate and aromatase inhibition therapy may fight breast cancer by blocking the use of estrogen by the tumor cells. Radiation therapy uses high energy x rays to kill tumor cells. Giving combination chemotherapy and radiation therapy with or without hormone therapy may be an effective treatment for hormone receptor-positive, HER2-positive, operable or locally advanced breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson, 650-723-0501.

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  • Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer Recruiting

    This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how HER2 mutated cancer responds to treatment with neratinib.

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  • Olaparib as Adjuvant Treatment in Patients With Germline BRCA Mutated High Risk HER2 Negative Primary Breast Cancer Recruiting

    Olaparib treatment in patients with germline BRCA1/2 mutations and high risk HER2 negative primary breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy

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  • 18F FPPRGD2 PET/CT or PET/MRI in Predicting Early Response in Patients With Cancer Receiving Anti-Angiogenesis Therapy Recruiting

    The purpose of the study is to conduct research of a new PET radiopharmaceutical in cancer patients. We will assess the uptake of this novel radiopharmaceutical in subjects with breast cancer, lung cancer, glioblastoma multiforme (GBM) and other cancers requiring antiangiogenesis treatment.

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  • Study of Fulvestrant +/- Everolimus in Post-Menopausal, Hormone-Receptor + Metastatic Breast Ca Resistant to AI Not Recruiting

    Post-menopausal women with hormone-receptor positive (HR+) metastatic breast cancer resistant to aromatase inhibitor (AI) therapy will be randomized to receive Fulvestrant (Faslodex) with Everolimus or Fulvestrant (Faslodex) with a placebo (no active ingredients). Fulvestrant has demonstrated activity when used as first, second, or third line endocrine therapy, making it an attractive therapy for combination with other agents. In addition, it is commonly reserved for use following disease progression on AI therapy. Everolimus is an orally administered drug that blocks a signaling pathway called "mTOR". "mTOR" acts as a regulator for many processes in the body, including cell growth. Blocking this pathway may have an effect on cell growth. The combination of a novel class of agents (mTOR inhibitors) and an established standard treatment for metastatic HR+ breast cancer may potentially increase the clinical benefit by targeting multiple different biological pathways.

    Stanford is currently not accepting patients for this trial. For more information, please contact Pei-Jen Chang, 650-725-0866.

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  • Study of the Glutaminase Inhibitor CB-839 in Solid Tumors Recruiting

    Many tumor cells, in contrast to normal cells, have been shown to require the amino acid glutamine to produce energy for growth and survival. To exploit the dependence of tumors on glutamine, CB-839, a potent and selective inhibitor of the first enzyme in glutamine utilization, glutaminase, will be tested in this Phase 1 study in patients with solid tumors. This study is an open-label Phase 1 evaluation of CB-839 in patients with advanced solid tumors. The study will be conducted in 2 parts. Part 1 is a dose escalation study enrolling patients with locally-advanced, metastatic and/or refractory solid tumors to receive CB-839 capsules orally twice or three times daily. In Part 2, patients with each of the following diseases will be enrolled: A) Triple-Negative Breast Cancer, B) Non-Small Cell Lung Cancer (adenocarcinoma), C) Renal Cell Cancer, D) Mesothelioma, E) Fumarate hydratase (FH)-deficient tumors, F) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), G) SDH-deficient non-GIST tumors, H) tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) or IDH2, and I) cMyc mutation tumors. As an extension of Parts 1 & 2, patients will be treated with CB-839 in combination with standard chemotherapy. Combination groups include: Pac-CB, CBE, CB-Erl, CBD, and CB-Cabo. Pac-CB: patients with locally-advanced or metastatic TNBC will be treated with paclitaxel and CB-839. CBE: patients with advanced clear cell RCC or papillary RCC will be treated with everolimus in combination with CB-839. CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. CBD: patients with NSCLC harboring KRAS mutation will be treated with docetaxel and CB-839. CB-Cabo: patients with histologically confirmed diagnosis of locally-advanced, inoperable or metastatic RCC treated with cabozantinib in combination with CB-839. All patients will be assessed for safety, pharmacokinetics (plasma concentration of drug), pharmacodynamics (inhibition of glutaminase), biomarkers (biochemical markers that may predict responsiveness in later studies), and tumor response.

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  • A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer Not Recruiting

    The main purpose of this study is to compare progression-free survival for women with hormone receptor positive (HR+), human epidermal growth factor receptor (HER2) negative advanced breast cancer receiving either abemaciclib+fulvestrant or fulvestrant alone. Participants will be randomized to abemaciclib or placebo in a 2:1 ratio. The study will last about 9 months for each participant.

    Stanford is currently not accepting patients for this trial. For more information, please contact Annabel Castaneda, 650-498-7977.

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  • An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of VX-970 in Combination With Cytotoxic Chemotherapy Recruiting

    An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics (PK) of VX-970 in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors

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  • A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study) Not Recruiting

    The purpose of this 2-stage, 2-cohort Phase 2 trial is to evaluate the safety and efficacy of talazoparib (also known as BMN 673) in subjects with locally advanced or metastatic breast cancer with a deleterious germline BRCA 1 or BRCA 2 mutation. Subjects will be assigned to either Cohort 1 or 2 based on prior chemotherapy for metastatic disease: - Cohort 1) Subjects with a documented PR or CR to a prior platinum-containing regimen for metastatic disease with disease progression > 8 weeks following the last dose of platinum; or - Cohort 2) Subjects who have received > 2 prior chemotherapy regimens for metastatic disease and who have had no prior platinum therapy for metastatic disease

    Stanford is currently not accepting patients for this trial. For more information, please contact Karen Lau, 650-723-0658.

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  • A Study of Trastuzumab Emtansine (Kadcyla) Plus Pertuzumab (Perjeta) Following Anthracyclines in Comparison With Trastuzumab (Herceptin) Plus Pertuzumab and a Taxane Following Anthracyclines as Adjuvant Therapy in Participants With Operable HER2-Positive Primary Breast Cancer Not Recruiting

    This two-arm, randomized, open-label, multicenter study will evaluate the efficacy and safety of trastuzumab emtansine in combination with pertuzumab versus trastuzumab in combination with pertuzumab and a taxane as adjuvant therapy in participants with human epidermal growth (HER) factor 2 (HER2)-positive primary invasive breast cancer. Following surgery and anthracycline-based chemotherapy, participants will receive either trastuzumab emtansine at a dose of 3.6 milligrams per kilogram (mg/kg) and pertuzumab at a dose of 420 milligrams (mg) intravenously (IV) every 3 weeks (q3w) or trastuzumab at a dose of 6 mg/kg and pertuzumab at a dose of 420 mg IV q3w in combination with a taxane.

    Stanford is currently not accepting patients for this trial. For more information, please contact Annabel Castaneda, 650-498-7977.

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  • Evaluation of Pharmacodynamic Effects of IT-pIL12-EP in Patients With TNBC Recruiting

    Intratumoral plasmid IL-12 electroporation (IT-pIL12-EP) will be administered to approximately 10 patients with triple negative breast cancer (TNBC) with cutaneous or subcutaneous disease. Patients will receive one complete cycle of therapy, consisting of local injection of plasmid IL-12 (pIL-12) followed immediately by electroporation (EP), into accessible tumor lesions. IT-pIL12-EP will be administered in Days 1, 5, and 8 of the single 28-day cycle.

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  • Talazoparib Beyond BRCA (TBB) Trial Recruiting

    The aim of this single-arm phase II clinical trial is to evaluate the anti-cancer activity of Talazoparib (also known as BMN 673) in patients with advanced breast cancer with specific genetic or tumor genomic alterations. Patients with either triple-negative or HER2-negative breast cancer are eligible.

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  • A Study Of PF-06647020 For Adult Patients With Advanced Solid Tumors Not Recruiting

    To assess the safety and tolerability at increasing dose levels of PF-06647020 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery Recruiting

    The PENELOPEB study is designed to demonstrate that in the background of standard anti-hormonal therapy palbociclib provides superior invasive disease-free survival (iDFS) compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be an attractive option with a favourable safety profile for these patients.

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  • A Phase 1/2 Study of MEDI4276 in Adults Subjects With Select HER2-expressing Advanced Solid Tumors. Recruiting

    This research study is designed to evaluate an experimental drug, MEDI4276, in treating breast and stomach (gastric) cancer.

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  • A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study) Recruiting

    The purpose of this open-label, 2:1 randomized phase III trial is to compare the safety and efficacy of talazoparib (also known as BMN 673) versus protocol-specific physician's choice in patients who have locally advanced and/or metastatic breast cancer with germline BRCA mutations.

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  • 18F-FSPG PET/CT for Cancer Patients on Therapy Not Recruiting

    The goal of this Phase II clinical trial is to further evaluate the ability of 18F-FSPG to diagnose, prognosticate, and evaluate response to therapy in patients with a wide variety of metastatic cancers.

    Stanford is currently not accepting patients for this trial. For more information, please contact Phuong Pham, 650-725-9810.

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  • A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Solid Tumors Not Recruiting

    This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in subjects with relapsed or refractory solid tumors.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Study of ABT-165 in Subjects With Advanced Solid Tumors Not Recruiting

    This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABT-165 in subjects with advanced solid tumors. The early clinical development plan for ABT-165 is based on the activity demonstrated in preclinical models.

    Stanford is currently not accepting patients for this trial. For more information, please contact Janet Pan, 650-723-0628.

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  • Doxorubicin Hydrochloride and Cyclophosphamide Followed by Paclitaxel With or Without Carboplatin in Treating Patients With Triple-Negative Breast Cancer Recruiting

    This randomized phase III trial studies how well doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel with or without carboplatin work in treating patients with triple-negative breast cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether doxorubicin hydrochloride and cyclophosphamide is more effective when followed by paclitaxel alone or paclitaxel and carboplatin in treating triple-negative breast cancer.

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  • A Study of Atezolizumab in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Participants With Previously Untreated Metastatic Triple-Negative Breast Cancer (IMpassion130) Recruiting

    This multicenter, randomized, double-blind study will evaluate the efficacy, safety, and pharmacokinetics of atezolizumab (MPDL3280A) administered with nab-paclitaxel compared with placebo in combination with nab-paclitaxel in participants with locally advanced or metastatic triple-negative breast cancer (TNBC) who have not received prior systemic therapy for metastatic breast cancer (mBC). The safety of single-agent nab-paclitaxel has been determined in previous studies of participants with mBC and the safety data to date suggest that atezolizumab can be safely combined with standard chemotherapy agents.

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  • Study of Niraparib in Combination With Pembrolizumab (MK-3475) in Patients With Triple-negative Breast Cancer or Ovarian Cancer Recruiting

    This Phase 1/2 study will evaluate the safety and efficacy of combination treatment with niraparib and pembrolizumab (MK-3475) in patients with advanced or metastatic triple-negative breast cancer or recurrent ovarian cancer. (KEYNOTE-162)

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  • Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer Not Recruiting

    This randomized phase III clinical trial studies how well tamoxifen citrate, anastrozole, letrozole, or exemestane with or without chemotherapy work in treating patients with breast cancer that has spread from where it began in the breast to surrounding normal tissue (invasive). Estrogen can cause the growth of breast cancer cells. Hormone therapy, using tamoxifen citrate, may fight breast cancer by blocking the use of estrogen by the tumor cells. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving tamoxifen citrate, anastrozole, letrozole, or exemestane is more effective with combination chemotherapy in treating patients with breast cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amy Isaacson, 650-723-0501.

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2016-17 Courses


All Publications

  • Tumor BRCA1 Reversion Mutation Arising During Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance. Clinical cancer research : an official journal of the American Association for Cancer Research Afghahi, A., Timms, K. M., Vinayak, S., Jensen, K. C., Kurian, A. W., Carlson, R. W., Chang, P. J., Schackmann, E. A., Hartman, A. R., Ford, J. M., Telli, M. e. 2017


    In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy.PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was re-sequenced in the residual surgical breast tumor tissue.Nineteen patients had a deleterious germline BRCA1/2 mutation and 4 had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA and W1712X mutations, respectively, with loss of heterozygosity at these loci in the pre-treatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14 amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy four months later revealed the identical reversion mutation, and the patient subsequently died of metastatic breast cancer.We report a BRCA1 reversion mutation in a newly diagnosed triple-negative breast cancer patient that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse and death.

    View details for DOI 10.1158/1078-0432.CCR-16-2174

    View details for PubMedID 28087643

  • Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer. Clinical cancer research Telli, M. L., Timms, K. M., Reid, J., Hennessy, B., Mills, G. B., Jensen, K. C., Szallasi, Z., Barry, W. T., Winer, E. P., Tung, N. M., Isakoff, S. J., Ryan, P. D., Greene-Colozzi, A., Gutin, A., Sangale, Z., Iliev, D., Neff, C., Abkevich, V., Jones, J. T., Lanchbury, J. S., Hartman, A., Garber, J. E., Ford, J. M., Silver, D. P., Richardson, A. L. 2016; 22 (15): 3764-3773


    BRCA1/2 mutated and some sporadic triple negative breast cancers (TNBCs) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed based on loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score {greater than or equal to}42 or BRCA1/2 mutation, with response to platinum-based therapy.In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted Residual Cancer Burden score of 0 or 1 (RCB 0/1) and pathologic complete response (pCR) (OR=4.96, p=0.0036; OR=6.52, p=0.0058). HR deficiency remained a significant predictor of RCB 0/1 when adjusted for clinical variables (OR=5.86, p=0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/1 and pCR (OR=10.18, p=0.0011; OR=17.00, p=0.0066). In a multivariable model of RCB 0/1, HR deficiency retained significance when clinical variables were included (OR=12.08, p=0.0017). When restricted to BRCA1/2 non-mutated tumors, response was higher in patients with high HRD scores: RCB 0/1 p=0.062, pCR p=0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/1 p=0.0039, pCR p=0.018 in the neoadjuvant cisplatin trials.HR deficiency identifies TNBC tumors, including BRCA1/2 non-mutated tumors more likely to respond to platinum-containing therapy.

    View details for DOI 10.1158/1078-0432.CCR-15-2477

    View details for PubMedID 26957554

  • Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity NATURE MEDICINE Burridge, P. W., Li, Y. F., Matsa, E., Wu, H., Ong, S., Sharma, A., Holmstrom, A., Chang, A. C., Coronado, M. J., Ebert, A. D., Knowles, J. W., Telli, M. L., Witteles, R. M., Blau, H. M., Bernstein, D., Altman, R. B., Wu, J. C. 2016; 22 (5): 547-556


    Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.

    View details for DOI 10.1038/nm.4087

    View details for Web of Science ID 000375514000018

    View details for PubMedID 27089514

  • Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105. Journal of clinical oncology Telli, M. L., Jensen, K. C., Vinayak, S., Kurian, A. W., Lipson, J. A., Flaherty, P. J., Timms, K., Abkevich, V., Schackmann, E. A., Wapnir, I. L., Carlson, R. W., Chang, P., Sparano, J. A., Head, B., Goldstein, L. J., Haley, B., Dakhil, S. R., Reid, J. E., Hartman, A., Manola, J., Ford, J. M. 2015; 33 (17): 1895-1901


    This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021).Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

    View details for DOI 10.1200/JCO.2014.57.0085

    View details for PubMedID 25847929

  • Insight or confusion: survival after response-guided neoadjuvant chemotherapy in breast cancer JOURNAL OF CLINICAL ONCOLOGY Telli, M. L. 2013; 31 (29): 3613-5
  • PARP inhibitors in cancer: moving beyond BRCA LANCET ONCOLOGY Telli, M. L. 2011; 12 (9): 827-828
  • Genetics of triple-negative breast cancer: Implications for patient care. Current problems in cancer Afghahi, A., Telli, M. L., Kurian, A. W. ; 40 (2-4): 130–40


    Patients with triple-negative breast cancer (TNBC), defined as lacking expression of the estrogen and progesterone receptors (ER/PR) and amplification of the HER2 oncogene, often have a more aggressive disease course than do patients with hormone receptor-positive breast cancer, including higher rates of visceral and central nervous system metastases, early cancer recurrences and deaths. Triple-negative breast cancer is associated with a young age at diagnosis and both African and Ashkenazi Jewish ancestry, the latter due to three common founder mutations in the highly penetrant cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2). In the past decade, there has been a surge both in genetic testing technology and in patient access to such testing. Advances in genetic testing have enabled more rapid and less expensive commercial sequencing than could be imagined only a few years ago. Massively parallel, next-generation sequencing allows the simultaneous analysis of many different genes. Studies of TNBC patients in the current era have revealed associations of TNBC with mutations in several moderate penetrance breast cancer susceptibility genes, including PALB2, BARD1, BRIP1, RAD51C and RAD51D. Interestingly, many of these genes, like BRCA1/2, are involved in homologous recombination DNA double-stranded repair. In this review, we summarize the current understanding of pathogenic germline gene mutations associated with TNBC and the early detection and prevention strategies for women at risk of developing this high-risk breast cancer subtype. Furthermore, we discuss recent the advances in targeted therapies for TNBC patients with a hereditary predisposition, including the role of poly (ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2 mutation-associated breast cancers.

    View details for DOI 10.1016/j.currproblcancer.2016.09.007

    View details for PubMedID 28340968

  • A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale. Future oncology Isakoff, S. J., Puhalla, S., Domchek, S. M., Friedlander, M., Kaufman, B., Robson, M., Telli, M. L., Diéras, V., Han, H. S., Garber, J. E., Johnson, E. F., Maag, D., Qin, Q., Giranda, V. L., Shepherd, S. P. 2016: -?


    Veliparib is an orally administered poly(ADP-ribose) polymerase inhibitor that is being studied in Phase I-III clinical trials, including Phase III studies in non-small-cell lung cancer, ovarian cancer and breast cancer. Tumor cells with deleterious BRCA1 or BRCA2 mutations are deficient in homologous recombination DNA repair and are intrinsically sensitive to platinum therapy and poly(ADP-ribose) polymerase inhibitors. We describe herein the design and rationale of a Phase II trial investigating whether the addition of veliparib to temozolomide or carboplatin/paclitaxel provides clinical benefit over carboplatin/paclitaxel with placebo in patients with locally recurrent or metastatic breast cancer harboring a deleterious BRCA1 or BRCA2 germline mutation (Trial registration: EudraCT 2011-002913-12, NCT01506609).

    View details for PubMedID 27739325

  • Lymph Node Ratio Analysis After Neoadjuvant Chemotherapy is Prognostic in Hormone Receptor-Positive and Triple-Negative Breast Cancer. Annals of surgical oncology Tsai, J., Bertoni, D., Hernandez-Boussard, T., Telli, M. L., Wapnir, I. L. 2016; 23 (10): 3310-3316


    Lymph node ratios (LNR), the proportion of positive lymph nodes over the number excised, both defined as ranges and single ratio values are prognostic of outcome. Little is known of the prognostic value of LNR after neoadjuvant chemotherapy (NAC) according to molecular subtype.From 2003 to 2014, patients who underwent definitive surgery after NAC were identified. LNR was calculated for node-positive patients who received axillary dissection or had at least 6 nodes removed. DFS was calculated using the Kaplan-Meier log rank test for yp N0-3 status, LNR categories (LNRC) ≤0.20 (low), 0.21-0.65 (intermediate), >0.65 (high), and single LNR values.Of 428 NAC recipients, 263 were node negative and 165 (38.6 %) node positive: ypN1 = 97 (58.8 %), ypN2 = 43 (26.1 %), and ypN3 = 25 (15.2 %). Among node-positive cancers, the median number of LN removed was 14 (range, 6-51) and the median LNR was 0.22 (range, 0.03-1.0). Nodal stage was inversely associated with 5-year DFS: 91.5 % (ypN0), 74.5 % (ypN1), 49.8 % (ypN2), and 50.7 % (ypN3) (p < 0.001). LNRC was similarly inversely associated with DFS: 69.1 % (low), 71.4 % (intermediate), 49.3 % (high) (p < 0.001). Significant associations between LNRC and DFS were demonstrated in hormone receptor (HR)-positive and triple negative breast cancer (TNBC) subtypes, p = 0.02 and p = 0.003. A single-value LNR ≤ 0.15 in node-positive, HR-positive (94.1 vs 67.7 %; p = 0.04) and TNBC (94.1 vs 47.8 %; p = 0.001) groups was also significant.Residual nodal disease after NAC, analyzed by LNRC or LNR = 0.15 cutoff value, is prognostic and can discriminate between favorable and unfavorable outcomes for HR-positive and TNBC cancers.

    View details for DOI 10.1245/s10434-016-5319-8

    View details for PubMedID 27401442

  • Acute, Unilateral Breast Toxicity From Gemcitabine in the Setting of Thoracic Inlet Obstruction. Journal of oncology practice / American Society of Clinical Oncology Weiskopf, K., Creighton, D., Lew, T., Caswell, J. L., Ouyang, D., Shah, A. T., Hofmann, L. V., Neal, J. W., Telli, M. L. 2016; 12 (8): 763-764

    View details for DOI 10.1200/JOP.2016.014241

    View details for PubMedID 27511721

  • Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) -Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline JOURNAL OF CLINICAL ONCOLOGY Denduluri, N., Somerfield, M. R., Eisen, A., Holloway, J. N., Hurria, A., King, T. A., Lyman, G. H., Partridge, A. H., Telli, M. L., Trudeau, M. E., Wolff, A. C. 2016; 34 (20): 2416-U186


    A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancers was identified for adaptation.The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability.On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members.Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

    View details for DOI 10.1200/JCO.2016.67.0182

    View details for Web of Science ID 000379127400013

    View details for PubMedID 27091714

  • Invasive Breast Cancer Version 1.2016 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M., Goldstein, L. J., Hudis, C. A., Isakoff, S. J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2016; 14 (3): 324-354


    Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This article outlines the NCCN Guidelines specific to breast cancer that is locoregional (restricted to one region of the body), and discusses the management of clinical stage I, II, and IIIA (T3N1M0) tumors. For NCCN Guidelines on systemic adjuvant therapy after locoregional management of clinical stage I, II and IIIA (T3N1M0) and for management for other clinical stages of breast cancer, see the complete version of these guidelines at

    View details for Web of Science ID 000371997900012

    View details for PubMedID 26957618

  • Breast Cancer After Hodgkin Lymphoma: The Price of Success. Oncology (Williston Park, N.Y.) Manzo, V., Dirbas, F., Telli, M. e. 2016; 30 (12)

    View details for PubMedID 27987199

  • Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers CANCER DISCOVERY Watkins, J., Weekes, D., Shah, V., Gazinska, P., Joshi, S., Sidhu, B., Gillett, C., Pinder, S., Vanoli, F., Jasin, M., Mayrhofer, M., Isaksson, A., Cheang, M. C., Mirza, H., Frankum, J., Lord, C. J., Ashworth, A., Vinayak, S., Ford, J. M., Telli, M. L., Grigoriadis, A., Tutt, A. N. 2015; 5 (5): 488-505


    Triple-negative breast cancers (TNBCs) are characterised by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that Allelic-imbalanced Copy Number Aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs as well as sensitising cancer cells to HR targeting therapies. Our data therefore provides a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability and an association with response to platinum-based chemotherapy in TNBC.

    View details for DOI 10.1158/2159-8290.CD-14-1092

    View details for Web of Science ID 000353700000022

    View details for PubMedID 25770156

  • Evolving treatment strategies for triple-negative breast cancer. Journal of the National Comprehensive Cancer Network Telli, M. 2015; 13 (5): 652-654


    Although not yet practice changing in early-stage triple-negative breast cancer, growing evidence suggests that neoadjuvant platinum-based therapy is active and that some patients may benefit from such an approach. Recent randomized phase III data suggests that carboplatin has comparable efficacy to docetaxel as first-line therapy in unselected advanced triple-negative breast cancer. In both settings, the efficacy of such treatment appears to be influenced by BRCA1/2 mutation status, with carriers of these mutations experiencing higher response rates. To optimize patient selection, biomarkers of response need to be incorporated into randomized clinical trials and validated. In addition to BRCA1/2, it is likely that measures of genomic instability and other germline biomarkers beyond BRCA1/2 may be associated with therapeutic sensitivity.

    View details for PubMedID 25995421

  • Breast Cancer Version 2.2015 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M., Goldstein, L. J., Hudis, C. A., Isakoff, S. J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2015; 13 (4): 448-475


    Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.

    View details for Web of Science ID 000352962200010

    View details for PubMedID 25870381

  • The future of breast cancer systemic therapy: the next 10 years JOURNAL OF MOLECULAR MEDICINE-JMM Telli, M. L., Sledge, G. W. 2015; 93 (2): 119-125


    Over the past 50 years, substantial progress has been made in the systemic treatment of early-stage and advanced breast cancer. The use of chemotherapy in the adjuvant and metastatic settings has demonstrated proven efficacy and it has been clearly demonstrated that targeting the estrogen receptor and human growth factor receptor 2 (HER2) is efficacious in early and advanced disease. Despite these advances, vexing clinical challenges remain particularly related to the treatment of triple-negative breast cancer (TNBC; estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, and HER2-negative) where little progress has been made therapeutically in more than a decade. While recurrences of hormone-responsive breast cancer are overall less common, late relapses after cessation of endocrine therapy are a more frequent occurrence in modern times and reflect the problem of underlying tumor dormancy that as yet has not been overcome. Multiple molecular tools are now available to interrogate the biology of breast cancer, though exactly how to make this information meaningful in the clinic has proven challenging, and molecularly driven clinical trials have faced feasibility challenges. In parallel, focus has expanded from tumor to host with the ability to ascertain underlying germline alterations, such as inherited BRCA1 and BRCA2 mutations, which may be responsible for breast cancer carcinogenesis and, importantly, may have implications for treatment. These clinical advances in germline genetics, made possible by both scientific investigation as well as the courts, still face challenges related to increasing encounters with variants of unknown significance and difficulty in predicting risks associated with less well-characterized inherited cancer predisposition syndromes. In this paper, we attempt to predict the next 10 years of breast cancer, in particular focusing on how the past serves as prologue to the future in this disease.

    View details for DOI 10.1007/s00109-014-1238-y

    View details for Web of Science ID 000349288800002

  • Breast Cancer, Version 1.2016. Journal of the National Comprehensive Cancer Network : JNCCN Gradishar, W. J., Anderson, B. O., Balassanian, R., Blair, S. L., Burstein, H. J., Cyr, A., Elias, A. D., Farrar, W. B., Forero, A., Giordano, S. H., Goetz, M., Goldstein, L. J., Hudis, C. A., Isakoff, S. J., Marcom, P. K., Mayer, I. A., McCormick, B., Moran, M., Patel, S. A., Pierce, L. J., Reed, E. C., Salerno, K. E., Schwartzberg, L. S., Smith, K. L., Smith, M. L., Soliman, H., Somlo, G., Telli, M., Ward, J. H., Shead, D. A., Kumar, R. 2015; 13 (12): 1475-85


    These NCCN Guideline Insights highlight the important updates to the systemic therapy recommendations in the 2016 NCCN Guidelines for Breast Cancer. In the most recent version of these guidelines, the NCCN Breast Cancer Panel included a new section on the principles of preoperative systemic therapy. In addition, based on new evidence, the panel updated systemic therapy recommendations for women with hormone receptor-positive breast cancer in the adjuvant and metastatic disease settings and for patients with HER2-positive metastatic breast cancer. This report summarizes these recent updates and discusses the rationale behind them.

    View details for PubMedID 26656517

  • (18)F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. Radiology Iagaru, A., Mosci, C., Shen, B., Chin, F. T., Mittra, E., Telli, M. L., Gambhir, S. S. 2014; 273 (2): 549-559


    Purpose To present data from the first prospective pilot phase trial of breast cancer participants imaged with fluorine 18 ((18)F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) (FPPRGD2), a radiopharmaceutical agent used in positron emission tomographic (PET) imaging. Materials and Methods The local institutional review board approved the HIPAA-compliant protocol. Written informed consent was obtained from each patient. Eight women (age range, 44-67 years; mean age, 54.3 years ± 8.8 [standard deviation]) with newly diagnosed or recurrent breast cancer were recruited between November 2010 and February 2011. (18)F-FPPRGD2 PET/computed tomographic (CT) and (18)F-fluorodeoxyglucose (FDG) PET/CT examinations were performed within 3 weeks of each other. Dynamic (18)F-FPPRGD2 PET and two whole-body static (18)F-FPPRGD2 PET/CT scans were obtained. During this time, vital signs and electrocardiograms were recorded at regular intervals. Blood samples were obtained before the injection of (18)F-FPPRGD2 and at 24 hours and 1 week after injection to evaluate for toxicity. A nonparametric version of multivariate analysis of variance was used to assess the safety outcome measures simultaneously across time points. A paired two-sample t test was performed to compare the maximum standardized uptake values (SUVmax). Results (18)F-FPPRGD2 was well tolerated, without noticeable changes in vital signs, on electrocardiograms, or in laboratory values. A total of 30 lesions were evaluated at (18)F-FDG PET/CT and (18)F-FPPRGD2 PET/CT. The primary breast lesions had (18)F-FPPRGD2 uptake with SUVmax of 2.4-9.4 (mean, 5.6 ± 2.8) 60 minutes after injection, compared with (18)F-FDG uptake with SUVmax of 2.8-18.6 (mean, 10.4 ± 7.2). Metastatic lesions also showed (18)F-FPPRGD2 uptake, with SUVmax of 2.4-9.7 (mean, 5.0 ± 2.3) at 60 minutes, compared with (18)F-FDG uptake with SUVmax of 2.2-14.6 (mean, 6.6 ± 4.2). Conclusion Data from this pilot phase study suggest that (18)F-FPPRGD2 is a safe PET radiopharmaceutical agent. Evaluation of (18)F-FPPRGD2 in participants with breast cancer demonstrated significant uptake in the primary lesion and in the metastases. Larger cohorts are required to confirm these preliminary findings. © RSNA, 2014.

    View details for DOI 10.1148/radiol.14140028

    View details for PubMedID 25033190

  • Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition. Breast cancer research Zhang, H., Cohen, A. L., Krishnakumar, S., Wapnir, I. L., Veeriah, S., Deng, G., Coram, M. A., Piskun, C. M., Longacre, T. A., Herrler, M., Frimannsson, D. O., Telli, M. L., Dirbas, F. M., Matin, A. C., Dairkee, S. H., Larijani, B., Glinsky, G. V., Bild, A. H., Jeffrey, S. S. 2014; 16 (2): R36-?


    Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and 5/6 primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.

    View details for DOI 10.1186/bcr3640

    View details for PubMedID 24708766

  • The role of platinum therapy in triple-negative breast cancer Breast Cancer Management Afghahi, A., Telli, M. L. 2014; 3 (4): 377-385

    View details for DOI 10.2217/bmt.14.21

  • Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting Telli, M. 2014; 34: e37-42


    Although characterization of triple-negative breast cancer (TNBC) using mRNA gene expression profiling has certainly provided important insights, the concept of targeting DNA repair defects with DNA damaging therapeutics such as platinum in TNBC has been advanced from studies focusing on both germline and somatic genetic alterations associated with this breast cancer subtype. A growing body of preclinical and clinical data suggests that platinum chemotherapy has a potential role to play in the treatment of both early-stage and advanced TNBC, though results are not yet definitive. Randomized clinical trials that incorporate biomarkers of response, including germline BRCA1 and BRCA2 mutation status as well as tumor-based measures of genomic "scarring" resulting from the accumulation of DNA damage in tumors with deficient repair capacity, will help to clarify the optimal use and activity of platinum in TNBC.

    View details for DOI 10.14694/EdBook_AM.2014.34.e37

    View details for PubMedID 24857126

  • Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC cancer Deng, G., Krishnakumar, S., Powell, A. A., Zhang, H., Mindrinos, M. N., Telli, M. L., Davis, R. W., Jeffrey, S. S. 2014; 14: 456-?


    Therapeutic decisions in cancer are generally guided by molecular biomarkers or, for some newer therapeutics, primary tumor genotype. However, because biomarkers or genotypes may change as new metastases emerge, circulating tumor cells (CTCs) from blood are being investigated for a role in guiding real-time drug selection during disease progression, expecting that CTCs will comprehensively represent the full spectrum of genomic changes in metastases. However, information is limited regarding mutational heterogeneity among CTCs and metastases in breast cancer as discerned by single cell analysis. The presence of disseminated tumor cells (DTCs) in bone marrow also carry prognostic significance in breast cancer, but with variability between CTC and DTC detection. Here we analyze a series of single tumor cells, CTCs, and DTCs for PIK3CA mutations and report CTC and corresponding metastatic genotypes.We used the MagSweeper, an immunomagnetic separation device, to capture live single tumor cells from breast cancer patients' primary and metastatic tissues, blood, and bone marrow. Single cells were screened for known hotspot mutations in exons 9 and 20 of the PIK3CA gene. Captured DTCs grown in cell culture were also sequenced for PIK3CA mutations.Among 242 individual tumor cells isolated from 17 patients and tested for mutations, 48 mutated tumor cells were identified in three patients. Single cell analyses revealed mutational heterogeneity among CTCs and tumor cells in tissues. In a patient followed serially, there was mutational discordance between CTCs, DTCs, and metastases, and among CTCs isolated at different time points. DTCs from this patient propagated in vitro contained a PIK3CA mutation, which was maintained despite morphological changes during 21 days of cell culture.Single cell analysis of CTCs can demonstrate genotypic heterogeneity, changes over time, and discordance from DTCs and distant metastases. We present a cautionary case showing that CTCs from any single blood draw do not always reflect metastatic genotype, and that CTC and DTC analyses may provide independent clinical information. Isolated DTCs remain viable and can be propagated in culture while maintaining their original mutational status, potentially serving as a future resource for investigating new drug therapies.

    View details for DOI 10.1186/1471-2407-14-456

    View details for PubMedID 24947048

  • Dynamic contrast-enhanced MRI-based biomarkers of therapeutic response in triple-negative breast cancer JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION Golden, D. I., Lipson, J. A., Telli, M. L., Ford, J. M., Rubin, D. L. 2013; 20 (6): 1059-1066


    To predict the response of breast cancer patients to neoadjuvant chemotherapy (NAC) using features derived from dynamic contrast-enhanced (DCE) MRI.60 patients with triple-negative early-stage breast cancer receiving NAC were evaluated. Features assessed included clinical data, patterns of tumor response to treatment determined by DCE-MRI, MRI breast imaging-reporting and data system descriptors, and quantitative lesion kinetic texture derived from the gray-level co-occurrence matrix (GLCM). All features except for patterns of response were derived before chemotherapy; GLCM features were determined before and after chemotherapy. Treatment response was defined by the presence of residual invasive tumor and/or positive lymph nodes after chemotherapy. Statistical modeling was performed using Lasso logistic regression.Pre-chemotherapy imaging features predicted all measures of response except for residual tumor. Feature sets varied in effectiveness at predicting different definitions of treatment response, but in general, pre-chemotherapy imaging features were able to predict pathological complete response with area under the curve (AUC)=0.68, residual lymph node metastases with AUC=0.84 and residual tumor with lymph node metastases with AUC=0.83. Imaging features assessed after chemotherapy yielded significantly improved model performance over those assessed before chemotherapy for predicting residual tumor, but no other outcomes.DCE-MRI features can be used to predict whether triple-negative breast cancer patients will respond to NAC. Models such as the ones presented could help to identify patients not likely to respond to treatment and to direct them towards alternative therapies.

    View details for DOI 10.1136/amiajnl-2012-001460

    View details for Web of Science ID 000325557600009

    View details for PubMedID 23785100

  • A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk BREAST CANCER RESEARCH AND TREATMENT Vinayak, S., Schwartz, E. J., Jensen, K., Lipson, J., Alli, B., McPherson, L., Fernandez, A. M., Sharma, V. B., Staton, A., Mills, M. A., Schackmann, E. A., Telli, M. L., Kardashian, A., Ford, J. M., Kurian, A. W. 2013; electronic publication ahead of print, October 30
  • Qualitative and quantitative image-based biomarkers of therapeutic response in triple-negative breast cancer. AMIA Summits on Translational Science proceedings AMIA Summit on Translational Science Golden, D. I., Lipson, J. A., Telli, M. L., Ford, J. M., Rubin, D. L. 2013; 2013: 62-?


    Experimental targeted treatments for neoadjuvant chemotherapy for triple-negative breast cancer are currently underway, and a current challenge is predicting which patients will respond to these therapies. In this study, we use data from dynamic contrast-enhanced MRI (DCE-MRI) images to predict whether patients with triple negative breast cancer will respond to an experimental neoadjuvant chemotherapy regimen. Using pre-therapy image-based features that are both qualitative (e.g., morphological BI-RADS categories) and quantitative (e.g., lesion texture), we built a model that was able to predict whether patients will have residual invasive cancer with lymph nodes metastases following therapy (receiver operating characteristic area under the curve of 0.83, sensitivity=0.73, specificity=0.83). This model's performance is at a level that is potentially clinically valuable for predicting which patients may or may not benefit from similar treatments in the future.

    View details for PubMedID 24303300

  • Prevalence, putative mechanisms, and current management of sleep problems during chemotherapy for cancer. Nature and science of sleep Palesh, O., Peppone, L., Innominato, P. F., Janelsins, M., Jeong, M., Sprod, L., Savard, J., Rotatori, M., Kesler, S., Telli, M., Mustian, K. 2012; 4: 151-162


    Sleep problems are highly prevalent in cancer patients undergoing chemotherapy. This article reviews existing evidence on etiology, associated symptoms, and management of sleep problems associated with chemotherapy treatment during cancer. It also discusses limitations and methodological issues of current research. The existing literature suggests that subjectively and objectively measured sleep problems are the highest during the chemotherapy phase of cancer treatments. A possibly involved mechanism reviewed here includes the rise in the circulating proinflammatory cytokines and the associated disruption in circadian rhythm in the development and maintenance of sleep dysregulation in cancer patients during chemotherapy. Various approaches to the management of sleep problems during chemotherapy are discussed with behavioral intervention showing promise. Exercise, including yoga, also appear to be effective and safe at least for subclinical levels of sleep problems in cancer patients. Numerous challenges are associated with conducting research on sleep in cancer patients during chemotherapy treatments and they are discussed in this review. Dedicated intervention trials, methodologically sound and sufficiently powered, are needed to test current and novel treatments of sleep problems in cancer patients receiving chemotherapy. Optimal management of sleep problems in patients with cancer receiving treatment may improve not only the well-being of patients, but also their prognosis given the emerging experimental and clinical evidence suggesting that sleep disruption might adversely impact treatment and recovery from cancer.

    View details for PubMedID 23486503

  • Chest Wall Leiomyosarcoma After Breast-Conservative Therapy for Early-Stage Breast Cancer in a Young Woman With Li-Fraumeni Syndrome JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Henry, E., Villalobos, V., Million, L., Jensen, K. C., West, R., Ganjoo, K., Lebensohn, A., Ford, J. M., Telli, M. L. 2012; 10 (8): 939-942


    Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

    View details for Web of Science ID 000307494000004

    View details for PubMedID 22878818

  • Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort BREAST CANCER RESEARCH AND TREATMENT Masciari, S., Dillon, D. A., Rath, M., Robson, M., Weitzel, J. N., Balmana, J., Gruber, S. B., Ford, J. M., Euhus, D., Lebensohn, A., Telli, M., Pochebit, S. M., Lypas, G., Garber, J. E. 2012; 133 (3): 1125-1130


    Breast cancer is the most common tumor in women with Li-Fraumeni Syndrome (LFS), an inherited cancer syndrome associated with germline mutations in the TP53 tumor suppressor gene. Their lifetime breast cancer risk is 49% by age 60. Breast cancers in TP53 mutation carriers recently have more often been reported to be hormone receptor and HER-2 positive by immunohistochemistry and FISH in small series. We seek to complement the existing small literature with this report of a histopathologic analysis of breast cancers from women with documented LFS. Unstained slides and paraffin-embedded tumor blocks from breast cancers from 39 germline TP53 mutation carriers were assembled from investigators in the LFS consortium. Central histology review was performed on 93% of the specimens by a single breast pathologist from a major university hospital. Histology, grade, and hormone receptor status were assessed by immunohistochemistry; HER-2 status was defined by immunohistochemistry and/or FISH. The 43 tumors from 39 women comprise 32 invasive ductal carcinomas and 11 ductal carcinomas in situ (DCIS). No other histologies were observed. The median age at diagnosis was 32 years (range 22-46). Of the invasive cancers, 84% were positive for ER and/or PR; and 81% were high grade. Sixty three percent of invasive and 73% of in situ carcinomas were positive for Her2/neu (IHC 3+ or FISH amplified). Of the invasive tumors, 53% were positive for both ER and HER2+; other ER/PR/HER2 combinations were observed. The DCIS were positive for ER and HER2 in 27% of the cases. This report of the phenotype of breast cancers from women with LFS nearly doubles the literature on this topic. Most DCIS and invasive ductal carcinomas in LFS are hormone receptor positive and/or HER-2 positive. These findings suggest that modern treatments may result in improved outcomes for women with LFS-associated breast cancer.

    View details for DOI 10.1007/s10549-012-1993-9

    View details for Web of Science ID 000305914900030

    View details for PubMedID 22392042

  • Underestimating Cardiac Toxicity in Cancer Trials: Lessons Learned? JOURNAL OF CLINICAL ONCOLOGY Witteles, R. M., Telli, M. 2012; 30 (16): 1916-1918

    View details for DOI 10.1200/JCO.2011.40.4012

    View details for Web of Science ID 000304596800010

    View details for PubMedID 22454419

  • Single Cell Profiling of Circulating Tumor Cells: Transcriptional Heterogeneity and Diversity from Breast Cancer Cell Lines PLOS ONE Powell, A. A., Talasaz, A. H., Zhang, H., Coram, M. A., Reddy, A., Deng, G., Telli, M. L., Advani, R. H., Carlson, R. W., Mollick, J. A., Sheth, S., Kurian, A. W., Ford, J. M., Stockdale, F. E., Quake, S. R., Pease, R. F., Mindrinos, M. N., Bhanot, G., Dairkee, S. H., Davis, R. W., Jeffrey, S. S. 2012; 7 (5)


    To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery.We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy.For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.

    View details for DOI 10.1371/journal.pone.0033788

    View details for Web of Science ID 000305335000005

    View details for PubMedID 22586443

  • Chemotherapy-Associated Cardiotoxicity: How Often Does it Really Occur and How Can it Be Prevented? HEART FAILURE CLINICS Witteles, R. M., Fowler, M. B., Telli, M. L. 2011; 7 (3): 333-?


    Cardiotoxicity remains the limiting factor for many forms of cancer therapy and is the focus of growing research and clinical emphasis. This article outlines the current clinical evidence for left ventricular dysfunction and heart failure for the two most important classes of cardiotoxic chemotherapeutic agents, examines the potential pitfalls that have led to underestimated rates of left ventricular dysfunction from these agents, and reviews strategies for screening for and providing prophylaxis against chemotherapy-associated left ventricular dysfunction.

    View details for DOI 10.1016/j.hfc.2011.03.005

    View details for Web of Science ID 000307494700006

    View details for PubMedID 21749885

  • Asian ethnicity and breast cancer subtypes: a study from the California Cancer Registry BREAST CANCER RESEARCH AND TREATMENT Telli, M. L., Chang, E. T., Kurian, A. W., Keegan, T. H., McClure, L. A., Lichtensztajn, D., Ford, J. M., Gomez, S. L. 2011; 127 (2): 471-478


    The distribution of breast cancer molecular subtypes has been shown to vary by race/ethnicity, highlighting the importance of host factors in breast tumor biology. We undertook the current analysis to determine population-based distributions of breast cancer subtypes among six ethnic Asian groups in California. We defined immunohistochemical (IHC) surrogates for each breast cancer subtype among Chinese, Japanese, Filipina, Korean, Vietnamese, and South Asian patients diagnosed with incident, primary, invasive breast cancer between 2002 and 2007 in the California Cancer Registry as: hormone receptor-positive (HR+)/HER2- [estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+), human epidermal growth factor receptor 2-negative (HER2-)], triple-negative (ER-, PR-, and HER2-), and HER2-positive (ER±, PR±, and HER2+). We calculated frequencies of breast cancer subtypes among Asian ethnic groups and evaluated their associations with clinical and demographic factors. Complete IHC data were available for 8,140 Asian women. Compared to non-Hispanic White women, Korean [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.5-2.2], Filipina (OR = 1.3, 95% CI = 1.2-1.5), Vietnamese (OR = 1.3, 95% CI = 1.1-1.6), and Chinese (OR = 1.1, 95% CI = 1.0-1.3) women had a significantly increased risk of being diagnosed with HER2-positive breast cancer subtypes after adjusting for age, stage, grade, socioeconomic status, histology, diagnosis year, nativity, and hospital ownership status. We report a significant ethnic disparity in HER2-positive breast cancer in a large population-based cohort enriched for Asian-Americans. Given the poor prognosis and high treatment costs of HER2-positive breast cancer, our results have implications for healthcare resource utilization, cancer biology, and clinical care.

    View details for DOI 10.1007/s10549-010-1173-8

    View details for Web of Science ID 000290227900017

    View details for PubMedID 20957431

  • Trastuzumab-Related Cardiac Dysfunction JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Telli, M. L., Witteles, R. M. 2011; 9 (2): 243-249


    The use of trastuzumab in the adjuvant and metastatic treatment of breast cancer is associated with both symptomatic and asymptomatic cardiotoxicity. The long-term significance of these events, isolating known cardiotoxic effects of anthracyclines from those of trastuzumab, and the appropriateness of referring to trastuzumab-related cardiotoxicity as reversible rather than responsive to trastuzumab withdrawal and heart failure medical therapy, are issues that continue to be debated. This article provides an overview of the available cardiac safety data from the major trastuzumab clinical trials in breast cancer, highlighting areas of ongoing controversy. Important recent data documenting the occurrence and prognostic use of cardiac troponin I elevations among patients treated with trastuzumab are placed into context with the mechanistic insight these data provide and the implications for clinical practice today.

    View details for Web of Science ID 000287942900005

    View details for PubMedID 21310845

  • Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies Are Clinicians Responding Optimally? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yoon, G. J., Telli, M. L., Kao, D. P., Matsuda, K. Y., Carlson, R. W., Witteles, R. M. 2010; 56 (20): 1644-1650


    The purpose of this study was to examine treatment practices for cancer therapy-associated decreased left ventricular ejection fraction (LVEF) detected on echocardiography and whether management was consistent with American College of Cardiology/American Heart Association guidelines.Patients treated with anthracyclines or trastuzumab are at risk of cardiotoxicity. Decreased LVEF represents a Class I indication for drug intervention according to American College of Cardiology/American Heart Association guidelines.Patients receiving anthracycline or trastuzumab at Stanford University from October 2005 to October 2007 and who had undergone echocardiography before and after receiving an anthracycline or trastuzumab were identified. Chart review examined chemotherapy regimens, cardiac risk factors, imaging results, concomitant medications, and cardiology consultations.Eighty-eight patients received therapy with an anthracycline or trastuzumab and had a pre-treatment and follow-up echocardiogram. Ninety-two percent were treated with anthracyclines, 17% with trastuzumab after an anthracycline, and 8% with trastuzumab without previous treatment with anthracycline. Mean baseline LVEF was 60%, with 14% having a baseline <55%. Forty percent had decreased LVEF (<55%) after anthracycline and/or trastuzumab treatment. Of these patients, 40% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 51% beta-blocker therapy, and 54% cardiology consultation. Of patients with asymptomatic decreased LVEF, 31% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 35% beta-blocker therapy, and 42% cardiology consultation. Of those with symptomatic decreased LVEF, 67% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 100% beta-blocker therapy, and 89% cardiology consultation.Many cancer survivors are not receiving treatment consistent with heart failure guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving cardiotoxic therapy.

    View details for DOI 10.1016/j.jacc.2010.07.023

    View details for Web of Science ID 000283737600007

    View details for PubMedID 21050974

  • PARP inhibitors in breast cancer. Clinical advances in hematology & oncology : H&O Telli, M. L., Ford, J. M. 2010; 8 (9): 629-635


    The therapeutic implications of DNA damage in cancer therapy have long been appreciated and form the basis of many successful cytotoxic chemotherapy and radiotherapy treatment strategies. A novel class of DNA repair defect targeted therapeutics that inhibit poly (ADP-Ribose) polymerase (PARP) are being rapidly developed in breast cancer based on exciting preliminary clinical activity as single agents in BRCA mutation-associated breast cancer and in combination with chemotherapy in triple-negative breast cancer. Though there is widespread enthusiasm to move these drugs forward quickly, much remains to be understood about the optimal use of the novel agents. Here we review the clinical development of PARP inhibitors in breast cancer and highlight clinical trials in progress. We also provide commentary on a series of outstanding questions in the field, the answers to which will be critical for the successful development of PARP inhibitor-based strategies in early- and late-stage breast cancer.

    View details for PubMedID 21157412

  • Novel Treatment Approaches for Triple-Negative Breast Cancer CLINICAL BREAST CANCER Telli, M. L., Ford, J. M. 2010; 10: E16-E22


    Triple-negative breast cancers share an aggressive biology, marked by increased recurrence risk and poorer survival compared with hormone receptor-positive subtypes. Few therapeutic trials have specifically focused on triple-negative breast cancer, and the treatment of patients with early-stage triple-negative breast cancer has changed little in the past decade. Over this time, however, attention has shifted to treatment approaches based on molecular subtypes of breast cancer, and investigation into the mechanistic underpinnings of these distinct subtypes has exploded. Converging preclinical rationales combined with early provocative clinical efficacy has focused recent attention on strategies targeting DNA repair defects for the treatment of patients with triple-negative and BRCA mutation-associated breast cancers. These developments are very promising and suggest that major advances in the targeted treatment of patients with triple-negative breast cancer are in sight. This review provides an overview of the clinical features of triple-negative breast cancer and current treatment strategies in the adjuvant setting. Mechanisms of DNA repair and the DNA damage response are reviewed to provide background for understanding novel approaches targeting DNA repair defects in this disease with DNA-damaging chemotherapeutic agents and poly(ADP-ribose) polymerase inhibitors. Ongoing studies, including those investigating the role of antiangiogenic therapies, are also reviewed.

    View details for DOI 10.3816/CBC.2010.s.003

    View details for Web of Science ID 000279318400003

    View details for PubMedID 20587403

  • Increasing Mastectomy Rates for Early-Stage Breast Cancer? Population-Based Trends From California JOURNAL OF CLINICAL ONCOLOGY Gomez, S. L., Lichtensztajn, D., Kurian, A. W., Telli, M. L., Chang, E. T., Keegan, T. H., Glaser, S. L., Clarke, C. A. 2010; 28 (10): E155-E157

    View details for DOI 10.1200/JCO.2009.26.1032

    View details for Web of Science ID 000276152200036

    View details for PubMedID 20159812

  • Longer Relative Telomere Length in Blood from Women with Sporadic and Familial Breast Cancer Compared with Healthy Controls CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gramatges, M. M., Telli, M. L., Balise, R., Ford, J. M. 2010; 19 (2): 605-613


    Telomeres cap the ends of chromosomes and are composed of a series of noncoding hexamer repeats. Telomeres protect the integrity of DNA coding sequences and are integral to the maintenance of genomic stability. Previous studies have shown an association between shortened lymphocyte telomeres and increased risk for specific cancers. However, the association between telomere length and breast cancer risk is less clear. We examined the relative telomere length (RTL) in blood from women with no personal or family history of cancer (controls) compared with different populations of women with breast cancer and women at high genetic risk for developing breast cancer. RTL was determined as the telomere to single gene copy number ratio assessed by quantitative PCR. Breast cancer cases (low risk, n = 40; high risk, n = 62) had significantly longer RTL compared with unaffected controls (n = 50; mean RTL = 1.11 versus 0.84; P < 0.0001). The assessment of risk by RTL quartile showed an increased risk for breast cancer with each longer quartile, with the most significant risk observed in the longest quartile (odds ratio, 23.3; confidence interval, 4.4-122.3; P < 0.0003). Women without breast cancer but at high risk due to family history (n = 30) also showed longer telomeres than controls (mean RTL = 1.09 versus 0.84; P < 0.0001). Our analysis supports previous findings of longer RTL in breast cancer cases compared with controls, and is the first to observe longer RTL in women without breast cancer identified as high risk based on family history.

    View details for DOI 10.1158/1055-9965.EPI-09-0896

    View details for Web of Science ID 000278403900035

    View details for PubMedID 20142254

  • First-Line Chemotherapy for Metastatic Breast Cancer CLINICAL BREAST CANCER Telli, M. L., Carlson, R. W. 2009; 9: S66-S72


    The selection of first-line chemotherapy for metastatic breast cancer (MBC) is complex because of the myriad of treatment options available and the inherent biologic heterogeneity of the disease. The potential treatment options are greatly influenced by estrogen and progesterone receptor and HER2 status of the tumor, and biopsy with reassessment of these markers at the time of disease recurrence is strongly recommended. Metastatic breast cancer is generally an incurable disease, with survival that could range from months to several years. Important but modest improvements in overall survival (OS) have been observed for women with MBC over the past few decades, in part because of improvements in systemic therapy. For women with endocrine-responsive disease, hormonal therapy is the appropriate initial treatment choice at the time of disease recurrence with rare exception. Initiation of systemic chemotherapy is appropriate for women with disease that is either hormone receptor negative, endocrine therapy refractory, or rapidly progressive with visceral involvement. The addition of trastuzumab to chemotherapy for women with HER2-positive breast cancer represents a clear standard of care. For HER2-negative MBC, sequential single-agent chemotherapy is preferred over combination therapy as a result of the more favorable toxicity profile and absence of a clinically significant improvement in survival with combination treatment. Many single-agent chemotherapeutic agents have activity in MBC, with most data supporting an anthracycline- or taxane-based approach. Bevacizumab in combination with chemotherapy prolongs progression-free survival in women with MBC, though its position in the first-line treatment of MBC relative to standard chemotherapy remains unclear at this time because of lack of OS benefit.

    View details for DOI 10.3816/CBC.2009.s.007

    View details for Web of Science ID 000267527100003

    View details for PubMedID 19596645

  • Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate ANNALS OF ONCOLOGY Telli, M. L., Witteles, R. M., Fisher, G. A., Srinivas, S. 2008; 19 (9): 1613-1618


    In the pivotal phase III metastatic renal cell carcinoma trial, updated data indicates that 21% of sunitinib-treated patients experienced a decline in left ventricular ejection fraction to below normal. This cardiotoxicity was reported to be reversible and without clinical sequelae. We conducted a retrospective analysis of our institutional experience of cardiotoxicity with sunitinib after observing a high incidence of symptomatic heart failure.Patients receiving sunitinib at Stanford University from 1 July 2004 to 1 July 2007 were identified. Medical records were reviewed and those patients experiencing symptomatic grade 3/4 left ventricular systolic dysfunction were identified. Potential cardiac risk factors were analyzed.Forty-eight patients treated with sunitinib were assessable. Seven patients experienced symptomatic grade 3/4 left ventricular dysfunction 22-435 days after initiation of sunitinib. Three patients had persistent cardiac dysfunction after discontinuation of sunitinib and initiation of heart failure therapy. A history of congestive heart failure, coronary artery disease and lower body mass index were factors associated with increased risk.Among patients treated with sunitinib at our institution, 15% developed symptomatic grade 3/4 heart failure. Future studies of sunitinib-related cardiotoxicity are urgently needed, particularly as the oncologic indications for this drug continue to expand.

    View details for DOI 10.1093/annonc/mdn168

    View details for Web of Science ID 000259505400015

    View details for PubMedID 18436521

  • Trastuzumab-related cardiotoxicity: Calling into question the concept of reversibility JOURNAL OF CLINICAL ONCOLOGY Telli, M. L., Hunt, S. A., Carlson, R. W., Guardino, A. E. 2007; 25 (23): 3525-3533


    To assess the spectrum and reversibility of the cardiotoxicity observed in the adjuvant trastuzumab trials.The design and efficacy of the major adjuvant trastuzumab trials was assessed, including the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group N9831, Herceptin Adjuvant, Breast Cancer International Research Group 006, and Finland Herceptin trials. The cardiotoxicity data were evaluated with a focus on the follow-up cardiac evaluations of women who were diagnosed with cardiotoxicity. Proposed mechanisms of trastuzumab-related cardiotoxicity were considered. The natural history of congestive heart failure (CHF) was reviewed with the goal of placing the trastuzumab experience in context.Up to 4% of patients enrolled onto the adjuvant trastuzumab trials experienced severe CHF during treatment. In these trials, early stopping rules that identified an unacceptable level of cardiotoxicity were never reached. Despite this, a large number of patients on these trials experienced some form of cardiotoxicity that ultimately required discontinuation of trastuzumab. Approximately 14% of patients in the NSABP B-31 trial discontinued trastuzumab because of asymptomatic decreases in left ventricular ejection fraction (LVEF). Results of follow-up cardiac evaluations of patients diagnosed with any degree of cardiotoxicity in the NSABP B-31 trial document that a clinically significant proportion of patients have sustained decrements in their LVEF to less than 50%.Adjuvant trastuzumab provides substantial benefits to patients with human epidermal growth factor receptor 2-positive breast cancer, however, competing immediate and long-term cardiovascular risks are a great concern. Continued cardiac follow-up of these women is of critical importance.

    View details for DOI 10.1200/JCO.2007.11.0106

    View details for Web of Science ID 000248744300023

    View details for PubMedID 17687157

  • Phyllodes tumors of the breast: natural history, diagnosis, and treatment. Journal of the National Comprehensive Cancer Network Telli, M. L., Horst, K. C., Guardino, A. E., Dirbas, F. M., Carlson, R. W. 2007; 5 (3): 324-330


    Phyllodes tumors of the breast are unusual fibroepithelial tumors that exhibit a wide range of clinical behavior. These tumors are categorized as benign, borderline, or malignant based on a combination of histologic features. The prognosis of phyllodes tumors is favorable, with local recurrence occurring in approximately 15% of patients overall and distant recurrence in approximately 5% to 10% overall. Wide excision with a greater than 1 cm margin is definitive primary therapy. Adjuvant systemic therapy is of no proven value. Patients with locally recurrent disease should undergo wide excision of the recurrence with or without subsequent radiotherapy.

    View details for PubMedID 17439760

  • Epidermal growth factor and angiotensin II regulation of extracellular signal-regulated protein kinase in rat liver epithelial WB cells BIOCHEMICAL PHARMACOLOGY Yang, L. J., Guo, Y. L., Trygankova, O., Li, Q. Y., Maloney, J. A., Steinhauer, M., Williamson, J. R. 1999; 57 (4): 425-432


    Activation of extracellular signal-regulated protein kinase (ERK) is considered essential for mitogenesis. In the present study, rat liver epithelial WB cells were used to investigate the relative roles of Ca2+, protein kinase C (PKC), and protein tyrosine phosphorylation in mitogenesis and activation of the ERK pathway stimulated by epidermal growth factor (EGF) and angiotensin II (Ang II). The sensitivity of the ERK pathway to Ca2+ was studied by using 1,2-bis (O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) to chelate intracellular Ca2+ and a low extracellular Ca2+ concentration to prevent Ca2+ influx. Agonist-induced PKC activation was diminished by inhibition of PKC by GF-109203X (bisindolylmaleimide) or by down-regulation of PKC by long-term treatment of the cells with phorbol myristate acetate (PMA). Our results show that although activation of PKC was critical for mitogenesis induced by Ang II or EGF, the initial activation of ERK by both agonists in these cells was essentially independent of PKC activation and was insensitive to Ca2+ mobilization. This is in contrast to the findings in some cell types that exhibit a marked dependency on mobilization of Ca2+ and/or PKC activation. On the other hand, an obligatory tyrosine phosphorylation step for activation of ERK was indicated by the use of protein tyrosine kinase inhibitors, which profoundly inhibited the activation of ERK by EGF, Ang II, and PMA. Additional experiments indicated that tyrosine phosphorylation by a cytosolic tyrosine kinase may represent a general mechanism for G-protein coupled receptor mediated ERK activation.

    View details for Web of Science ID 000078201600012

    View details for PubMedID 9933031