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1. Helping ourselves, helping others: the Young Women’s Breast Cancer Study (YWS) – a multisite prospective cohort study to advance the understanding of breast cancer diagnosed in women aged 40 years and younger

Author

Lidia Schapira, Yue Zheng, Laura Collins, Ann H Partridge, Jeffrey Peppercorn, Virginia F Borges, Rulla M Tamimi, Gregory J Kirkner, Eric P Winer, Kathryn Ruddy, Shoshana M Rosenberg, Philip D Poorvu, Craig Snow, Meghan E Meyer, Steven Come, Ellen Warner, and Shari Gelber

Subjects
Medicine
Abstract

Purpose Compared with older women diagnosed with breast cancer, younger women are more likely to die of breast cancer and more likely to suffer psychosocially in both the short-term and long term. The Young Women’s Breast Cancer Study (YWS) is a multisite prospective cohort study established to address gaps in our knowledge about this vulnerable and understudied population.Participants The YWS enrolled 1302 women newly diagnosed with stages 0–IV breast cancer at age 40 years or younger at 13 academic and community sites in North America between 2006 and 2016. Longitudinal patient-reported outcome data are complemented by clinical data abstraction and biospecimen collection at multiple timepoints.Findings to date Key findings related to fertility include that nearly 40% of participants were interested in pregnancy following diagnosis; of those who reported interest, 10% pursued fertility preservation. Overall, approximately 10% of YWS participants became pregnant in the first 5 years after diagnosis; follow-up is ongoing for pregnancies after 5 years. Studies focused on psychosocial outcomes have characterised quality of life, post-traumatic stress and fear of recurrence, with findings detailing the factors associated with the substantial psychosocial burden many young women face during and following active treatment. Multiple studies have leveraged YWS biospecimens, including whole-exome sequencing of tumour analyses that revealed that select somatic alterations occur at different frequencies in young (age≤35) versus older women with luminal A breast cancer, and a study that explored clonal hematopoiesis of indeterminate potential found it to be rare in young survivors.Future plans With a median follow-up of approximately 10 years, the cohort is just maturing for many relevant long-term outcomes and provides outstanding opportunities to further study and build collaborations to address gaps in our knowledge, with the ultimate objective to improve care and outcomes for young women with breast cancer.Trial registration number NCT01468246.

Published
2024
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2. Contribution of tumour and immune cells to PD‐L1 expression as a predictive biomarker in metastatic triple‐negative breast cancer: exploratory analysis from KEYNOTE‐119

Author

Javier Cortes, Eric P Winer, Oleg Lipatov, Seock‐Ah Im, Anthony Gonçalves, Eva Muñoz‐Couselo, Keun Seok Lee, Peter Schmid, Kenji Tamura, Laura Testa, Isabell Witzel, Shoichiro Ohtani, Stephanie Hund, Karina Kulangara, Vassiliki Karantza, Jaime A Mejia, Junshui Ma, Petar Jelinic, Lingkang Huang, Scott K Pruitt, and Kenneth Emancipator

Subjects
pembrolizumab, PD‐L1, triple‐negative breast cancer, Pathology, RB1-214
Abstract

Abstract The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD‐L1) expression, as quantified by combined positive score (CPS; PD‐L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple‐negative breast cancer (mTNBC) in the phase 3 KEYNOTE‐119 study. This exploratory analysis was conducted to determine whether the expression of PD‐L1 on tumour cells contributes to the predictive value of PD‐L1 CPS in mTNBC. PD‐L1 expression in tumour samples was assessed using PD‐L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD‐L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58–0.80) for CPS, 0.55 (95% CI = 0.46–0.64) for TPS, and 0.67 (95% CI = 0.56–0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression‐free survival, and overall survival. Data from this exploratory analysis suggest that, although PD‐L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD‐L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD‐L1 expression) may improve prediction. PD‐L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.

Published
2024
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3. Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer

Author

Sara M Tolaney, Tianyu Li, Edward T Richardson, Judith Agudo, Elizabeth A Mittendorf, Beth Overmoyer, Eric P Winer, Adrienne G Waks, Tanya E Keenan, Nabihah Tayob, Gerburg M Wulf, Victoria Attaya, Leilani Anderson, Ian E Krop, and Eliezer M Van Allen

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.Methods This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored.Results 20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort.Conclusions T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer.Trial registration number NCT03032107.

Published
2022
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4. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer

Author

Adrienne G. Waks, Neelam V. Desai, Tianyu Li, Philip D. Poorvu, Ann H. Partridge, Natalie Sinclair, Laura M. Spring, Meredith Faggen, Michael Constantine, Otto Metzger, Jillian Alberti, Julia Deane, Shoshana M. Rosenberg, Elizabeth Frank, Sara M. Tolaney, Ian E. Krop, Nadine M. Tung, Nabihah Tayob, Tari A. King, Elizabeth A. Mittendorf, and Eric P. Winer

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract De-escalating adjuvant therapy following pathologic complete response (pCR) to an abbreviated neoadjuvant regimen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer is the focus of international research efforts. However, the feasibility of this approach and its appeal to patients and providers had not been formally investigated. We aimed to assess adherence to de-escalated adjuvant antibody doublet therapy (trastuzumab and pertuzumab [HP], without chemotherapy) among patients with pCR following neoadjuvant paclitaxel/HP (THP). In this single-arm prospective trial, patients with treatment-naïve stage II-III HER2+ breast cancer received neoadjuvant weekly paclitaxel ×12 and HP every 3 weeks ×4. The primary endpoint was receipt of adjuvant non-HER2-directed cytotoxic chemotherapy. Ninety-eight patients received ≥1 dose of THP on study. Patients had median age of 50 years, 86% had stage II tumors, and 34% were hormone receptor-negative. Five patients had incomplete clinical response following THP and received doxorubicin and cyclophosphamide before surgery; they were classified as non-pCR and censored from further analyses. The overall pCR rate was 56.7%. Among patients with pCR, the adherence rate to de-escalated antibody-only therapy (HP) was 98.2% (95% CI 90.3–100.0%), and the primary feasibility endpoint was reached. The majority of patients felt positive or neutral about their adjuvant treatment plans. With brief follow-up (median 19.1 months), there were no breast cancer recurrences. De-escalation of adjuvant chemotherapy among patients who experience pCR in early-stage HER2+ breast cancer is a practicable approach for both patients and physicians. Planned and ongoing prospective trials will determine the long-term efficacy of this approach. Trial registration clinicaltrials.gov, NCT03716180, https://clinicaltrials.gov/ct2/show/NCT03716180 .

Published
2022
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5. p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases

Author

Jing Ni, Sheheryar Kabraji, Shaozhen Xie, Yanzhi Wang, Peichen Pan, Xiaofang He, Zongming Liu, Jose Palbo Leone, Henry W. Long, Myles A. Brown, Eric P. Winer, Deborah A. R. Dillon, Nancy U. Lin, and Jean J. Zhao

Subjects
Science
Abstract

HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.

Published
2022
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6. Cardiac outcomes of subjects on adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT) study (TBCRC033): a randomized controlled trial

Author

Romualdo Barroso-Sousa, Paolo Tarantino, Nabihah Tayob, Chau Dang, Denise A. Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Jiani Hu, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Frederick Briccetti, Bryan Schneider, Audrey Merrill Garrett, Kelly Marcom, Kathy Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta Liu, Kathryn J. Ruddy, Yue Zheng, Shoshana M. Rosenberg, Richard D. Gelber, Lorenzo Trippa, William Barry, Michelle DeMeo, Harold Burstein, Ann Partridge, Eric P. Winer, Ian Krop, and Sara M. Tolaney

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3–4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed. Clinical Trial Registration: ClinicalTrials.gov, NCT01853748

Published
2022
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7. Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer

Author

Tanya E. Keenan, Jennifer L. Guerriero, Romualdo Barroso-Sousa, Tianyu Li, Tess O’Meara, Anita Giobbie-Hurder, Nabihah Tayob, Jiani Hu, Mariano Severgnini, Judith Agudo, Ines Vaz-Luis, Leilani Anderson, Victoria Attaya, Jihye Park, Jake Conway, Meng Xiao He, Brendan Reardon, Erin Shannon, Gerburg Wulf, Laura M. Spring, Rinath Jeselsohn, Ian Krop, Nancy U. Lin, Ann Partridge, Eric P. Winer, Elizabeth A. Mittendorf, David Liu, Eliezer M. Van Allen, and Sara M. Tolaney

Subjects
Science
Abstract

A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

Published
2021
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8. Nivolumab in combination with cabozantinib for metastatic triple-negative breast cancer: a phase II and biomarker study

Author

Romualdo Barroso-Sousa, Tanya E. Keenan, Tianyu Li, Nabihah Tayob, Lorenzo Trippa, Ricardo G. Pastorello, Edward T. Richardson III, Deborah Dillon, Zohreh Amoozgar, Beth Overmoyer, Stuart J. Schnitt, Eric P. Winer, Elizabeth A. Mittendorf, Eliezer Van Allen, Dan G. Duda, and Sara M. Tolaney

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract This single-arm phase II study investigated the efficacy and safety of cabozantinib combined with nivolumab in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was objective response rate (ORR) by RECIST 1.1. Biopsies at baseline and after cycle 1 were analyzed for tumor-infiltrating lymphocytes (TILs), PD-L1, and whole-exome and transcriptome sequencing. Only 1/18 patients achieved a partial response (ORR 6%), and the trial was stopped early. Toxicity led to cabozantinib dose reduction in 50% of patients. One patient had a PD-L1-positive tumor, and three patients had TILs > 10%. The responding patient had a PD-L1-negative tumor with low tumor mutational burden but high TILs and enriched immune gene expression. High pretreatment levels of plasma immunosuppressive cytokines, chemokines, and immune checkpoint molecules were associated with rapid progression. Although this study did not meet its primary endpoint, immunostaining, genomic, and proteomic studies indicated a high degree of tumor immunosuppression in this mTNBC cohort.

Published
2021
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9. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: final 10-year analysis of the open-label, single-arm, phase 2 APT trial

Author

Sara M Tolaney, Paolo Tarantino, Noah Graham, Nabihah Tayob, Laia Parè, Guillermo Villacampa, Chau T Dang, Denise A Yardley, Beverly Moy, P Kelly Marcom, Kathy S Albain, Hope S Rugo, Matthew J Ellis, Iuliana Shapira, Antonio C Wolff, Lisa A Carey, Romualdo Barroso-Sousa, Patricia Villagrasa, Michelle DeMeo, Molly DiLullo, Jorge Gomez Tejeda Zanudo, Jakob Weiss, Nikhil Wagle, Ann H Partridge, Adrienne G Waks, Clifford A Hudis, Ian E Krop, Harold J Burstein, Aleix Prat, and Eric P Winer

Subjects
Oncology
Published
2023

10. Survival in male breast cancer over the past 3 decades

Author

José P Leone, Rachel A Freedman, Julieta Leone, Sara M Tolaney, Carlos T Vallejo, Bernardo A Leone, Eric P Winer, Nancy U Lin, and Michael J Hassett

Subjects
Cancer Research, Oncology
Abstract

Background Breast cancer mortality in women has declined statistically significantly over the past several years. In men, it is unclear whether survival has changed over time. We evaluated changes in breast cancer–specific survival (BCSS) and overall survival (OS) in male breast cancer over the past 3 decades. Methods We evaluated men diagnosed with breast cancer between 1988 and 2017, reported in the Surveillance, Epidemiology, and End Results registry. Patients were categorized into 3 groups by year of diagnosis: 1988-1997, 1998-2007, and 2008-2017. BCSS and OS were estimated by Kaplan-Meier, and differences between groups were compared by log-rank test. Multivariable Cox regression evaluated the independent association of year of diagnosis with BCSS and OS. All tests were 2-sided. Results We included 8481 men. Overall, BCSS at 5 years was 83.69%, 83.78%, and 84.41% in groups 1988-1997, 1998-2007, and 2008-2017, respectively (P = .86). There was no statistically significant difference in BCSS between the 3 groups within each stage of disease. Among all patients, OS at 5 years was 64.61%, 67.31%, and 69.05% in groups 1988-1997, 1998-2007, and 2008-2017, respectively (P = .01). In adjusted Cox models, each additional year of diagnosis had no statistically significant association with BCSS (hazard ratio = 1.00, 95% confidence interval = 0.99 to 1.01, P = .75), but there was statistically significant improvement in OS (hazard ratio = 0.99, 95% CI = 0.98 to 0.99, P = .009). Conclusions Over the past 3 decades, there has been no statistically significant improvement in BCSS in male breast cancer. Changes in OS over time are consistent with increasing life expectancy. Efforts to improve BCSS in male breast cancer are warranted.

Published
2022

11. Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer

Author

Junko Tsuji, Tianyu Li, Albert Grinshpun, Tim Coorens, Douglas Russo, Leilani Anderson, Rebecca Rees, Agostina Nardone, Candace Patterson, Niall J. Lennon, Carrie Cibulskis, Ignaty Leshchiner, Nabihah Tayob, Sara M. Tolaney, Nadine Tung, Donald P. McDonnell, Ian E. Krop, Eric P. Winer, Chip Stewart, Gad Getz, and Rinath Jeselsohn

Subjects
Cancer Research, Treatment Outcome, Receptors, Estrogen, Oncology, Receptor, ErbB-2, Antineoplastic Combined Chemotherapy Protocols, Exome Sequencing, Liquid Biopsy, Humans, Female, Breast Neoplasms, Article
Abstract

Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. Patients and Methods: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). Results: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0–7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5–13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. Conclusions: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.

Published
2022

12. Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases

Author

Sheheryar Kabraji, Jing Ni, Sarah Sammons, Tianyu Li, Amanda E.D. Van Swearingen, Yanzhi Wang, Alyssa Pereslete, Liangge Hsu, Pamela J. DiPiro, Chris Lascola, Heather Moore, Melissa Hughes, Akshara S. Raghavendra, Maria Gule-Monroe, Rashmi K. Murthy, Eric P. Winer, Carey K. Anders, Jean J. Zhao, and Nancy U. Lin

Subjects
Cancer Research, Immunoconjugates, Receptor, ErbB-2, Brain Neoplasms, Breast Neoplasms, Trastuzumab, Antibodies, Monoclonal, Humanized, Article, Cohort Studies, Treatment Outcome, Oncology, Humans, Female, Camptothecin, Prospective Studies, Retrospective Studies
Abstract

Purpose: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. Experimental Design: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. Results: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1–resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3–16.2) months, with 42% (7/17) remaining on treatment at data cutoff. Conclusions: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8

Published
2022

13. Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

Author

Marla Lipsyc-Sharf, Elza C. de Bruin, Katheryn Santos, Robert McEwen, Daniel Stetson, Ashka Patel, Gregory J. Kirkner, Melissa E. Hughes, Sara M. Tolaney, Ann H. Partridge, Ian E. Krop, Charlene Knape, Ute Feger, Giovanni Marsico, Karen Howarth, Eric P. Winer, Nancy U. Lin, and Heather A. Parsons

Subjects
Cancer Research, Neoplasm, Residual, Oncology, Receptor, ErbB-2, Mutation, Biomarkers, Tumor, Humans, Triple Negative Breast Neoplasms, Prospective Studies, Neoplasm Recurrence, Local, Circulating Tumor DNA
Abstract

PURPOSE To examine the prevalence and dynamics of circulating tumor DNA (ctDNA) and its association with metastatic recurrence in patients with high-risk early-stage hormone receptor–positive breast cancer (HR+ BC) more than 5 years from diagnosis. METHODS We enrolled 103 patients with high-risk stage II-III HR+ BC diagnosed more than 5 years prior without clinical evidence of recurrence. We performed whole-exome sequencing (WES) on primary tumor tissue to identify somatic mutations tracked via a personalized, tumor-informed ctDNA test to detect minimal residual disease (MRD). We collected plasma at the time of consent and at routine visits every 6-12 months. Patients were followed for clinical recurrence. RESULTS In total, 85 of 103 patients had sufficient tumor tissue; of them, 83 of 85 (97.6%) patients had successful whole-exome sequencing. Personalized ctDNA assays were designed targeting a median of 36 variants to test 219 plasma samples. The median time from diagnosis to first sample was 8.4 years. The median follow-up was 10.4 years from diagnosis and 2.0 years from first sample. The median number of plasma samples per patient was two. Eight patients (10%) had positive MRD testing at any time point. Six patients (7.2%) developed distant metastatic recurrence, all of whom were MRD-positive before overt clinical recurrence, with median ctDNA lead time of 12.4 months. MRD was not identified in one patient (1.2%) with local recurrence. Two of eight MRD-positive patients had not had clinical recurrence at last follow-up. CONCLUSION In this prospective study, in patients with high-risk HR+ BC in the late adjuvant setting, ctDNA was identified a median of 1 year before all cases of distant metastasis. Future studies will determine if ctDNA-guided intervention in patients with HR+ BC can alter clinical outcomes.

Published
2023

14. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Author

Viktor A. Adalsteinsson, Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah C. Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M. Francis, Cheng-Zhong Zhang, Ofir Cohen, Coyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O’Connor, Seong H. Jeong, Rachel Leeson, Rachel M. Barry, Joseph F. Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G. Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M. Oliver, Lori Marini, Adrienne G. Waks, Lauren C. Harshman, Sara M. Tolaney, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary-Ellen Taplin, Cory M. Johannessen, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz, J. Christopher Love, and Matthew Meyerson

Subjects
Science
Abstract

Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

Published
2017
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15. A Distinct Chromatin State Drives Therapeutic Resistance in Invasive Lobular Breast Cancer

Author

Agostina Nardone, Xintao Qiu, Sandor Spisak, Zsuzsanna Nagy, Ariel Feiglin, Avery Feit, Gabriela Cohen Feit, Yingtian Xie, Alba Font-Tello, Cristina Guarducci, Francisco Hermida-Prado, Sudeepa Syamala, Klothilda Lim, Miguel Munoz Gomez, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Aysegul Ors, Hisham Mohammed, Paloma Cejas, Jane B. Brock, Matthew L. Freedman, Eric P. Winer, Xiaoyong Fu, Rachel Schiff, Henry W. Long, Otto Metzger Filho, and Rinath Jeselsohn

Subjects
Carcinoma, Lobular, Tamoxifen, Cancer Research, Receptors, Estrogen, Oncology, Drug Resistance, Neoplasm, Carcinoma, Ductal, Breast, Humans, Breast Neoplasms, Female, Prognosis, Chromatin, Article
Abstract

Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor–positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1–estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1–ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1–ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. Significance: A unique FOXA1–ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668

Published
2022

18. Novel therapy in Acute myeloid leukemia (AML): moving toward targeted approaches

Author

Eric S. Winer and Richard M. Stone

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality. While progress has been made in the understanding of the genetic and molecular biology of the disease, the standard of care for patients had only changed minimally over the past 40 years. Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment. In this review, we discuss the recent results of completed or ongoing clinical trials with these novel therapeutic agents in AML.

Published
2019
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19. Impact of Neoadjuvant Paclitaxel/Trastuzumab/Pertuzumab on Breast Tumor Downsizing for Patients with HER2+ Breast Cancer: Single-Arm Prospective Clinical Trial

Author

Anna Weiss, Tianyu Li, Neelam V Desai, Nadine M Tung, Philip D Poorvu, Ann H Partridge, Faina Nakhlis, Laura Dominici, Natalie Sinclair, Laura M Spring, Meredith Faggen, Michael Constantine, Ian E Krop, Michelle DeMeo, Eileen Wrabel, Jillian Alberti, Sona Chikarmane, Nabihah Tayob, Tari A King, Sara M Tolaney, Eric P Winer, Elizabeth A Mittendorf, and Adrienne G Waks

Subjects
Surgery
Published
2023

20. Extended adjuvant endocrine therapy in a longitudinal cohort of young breast cancer survivors

Author

Tal Sella, Yue Zheng, Shoshana M. Rosenberg, Kathryn J. Ruddy, Shari I. Gelber, Rulla M. Tamimi, Jeffrey M. Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Lisa A. Carey, Eric P. Winer, and Ann H. Partridge

Subjects
Oncology, Pharmacology (medical), Radiology, Nuclear Medicine and imaging
Abstract

Extended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women’s Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006–2016. Women with stage I–III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6–8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81–4.51; III v. I: OR: 3.73, 95%CI: 1.87–7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16–6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.

Published
2023

21. Supplemental Figure 9 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S9

Published
2023

22. Data from Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial

Author

Jeffrey A. Meyerhardt, Charles S. Fuchs, Frank B. Hu, Pamela S. Douglas, Tara Sanft, Thomas A. Abrams, Kimmie Ng, Eric P. Winer, Sara M. Tolaney, Maura Harrigan, Brenda Cartmel, Alexandra Sorrentino, Michael N. Pollak, Nancy Campbell, Lee W. Jones, Melinda L. Irwin, Jennifer A. Ligibel, Sui Zhang, and Justin C. Brown

Abstract

Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [−30.2%; 95% confidence interval (CI), −50.3, −1.0] and IL6 (−30.9%; 95% CI, −47.3, −9.5) but did not change sTNFαR2 (1.0%; 95% CI, −10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (−13.9%; 95% CI, −40.0, 23.4), sTNFαR2 (−10.4%; 95% CI, −21.3, 2.0), or IL6 (−22.9%; 95% CI, −42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (−13.1%; 95% CI, −22.9, −1.0) and IL6 (−38.7%; 95% CI, −52.3, −18.9) but did not change hs-CRP (−20.5%; 95% CI, −44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.

Published
2023

23. Supplementary Fig. S1 from Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab

Author

Ian E. Krop, Eric P. Winer, Franziska Michor, Kornelia Polyak, Tari A. King, Leila Russo, Patrizia Dell'Orto, Aditya Bardia, Michelle K. DeMeo, Eileen Wrabel, Adrienne G. Waks, Laura M. Spring, Carlos L. Arteaga, Vandana G. Abramson, Ingrid A. Mayer, Denise A. Yardley, Lorenzo Trippa, Shayna Stein, Giuseppe Viale, and Otto Metzger Filho

Abstract

Pattern of HER2 amplification in the subset of HER2 heterogeneous tumors. Heatmap generated using data from central pathology evaluation of HER2 heterogeneity. The graphic includes patients classified as HER2 heterogeneous depicted in each row. The color code to the right of the heatmap refers to the percentage of HER2 amplified cells per core biopsy tumor area. Core biopsy tumor areas, A, B and C were obtained from core biopsy site 1 and D, E and F from core biopsy site 2.

Published
2023

24. Data from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations—in AKT1, RAS, and AURKA—have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients.Significance:We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079

Published
2023

25. Supplementary Table S2 from Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab

Author

Ian E. Krop, Eric P. Winer, Franziska Michor, Kornelia Polyak, Tari A. King, Leila Russo, Patrizia Dell'Orto, Aditya Bardia, Michelle K. DeMeo, Eileen Wrabel, Adrienne G. Waks, Laura M. Spring, Carlos L. Arteaga, Vandana G. Abramson, Ingrid A. Mayer, Denise A. Yardley, Lorenzo Trippa, Shayna Stein, Giuseppe Viale, and Otto Metzger Filho

Abstract

FISH raw counts

Published
2023

26. Supplemental Figure 8 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S8

Published
2023

27. Supplementary Table S3 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Author

William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos

Abstract

Summary of clinically informative (TARGET) genes.

Published
2023

28. Supplemental Figure 5 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S5

Published
2023

29. Supplemental Figure 4 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S4

Published
2023

30. Supplementary Methods, Figures S1 - S20 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Author

William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos

Abstract

Supplementary Methods, Figures S1 - S20. Figure S1. Branched evolution leads to tissue-sampling bias in primary tumor samples. Figure S2. Results of ABSOLUTE on samples from patient 418. Figure S3. 2D Bayesian clustering analysis of point-mutation CCF distributions in case 418. Figure S4. Bayesian clustering of private point-mutation CCF distributions in all sequenced tissue samples from case 418. Figure S5. Genetic alterations supporting phylogeny construction in case 418. Figure S6. Phylogenetic tree for case 418 Figure S7. Evolutionary relationships between primary tumor-samples and brain metastasis samples Figure S8. Detection of homozygous deletion in CDKN2A in the brain metastasis of case 24. Figure S9. Amplification of FGFR1 and MYC detected in the brain metastasis of case 331. Figure S10. Additional alterations under investigation for association with various targeted therapies. Figure S11. Power for paired-detection of somatic mutations. Figure S12. Amplification of CCNE1 detected in the brain metastasis of case 314. Figure S13. Amplification of EGFR detected in the brain metastasis of case 314. Figure S14. Amplification of MYC detected in the brain metastasis of case 308. Figure S15. Amplification of MYC detected in the brain metastasis of case 138. Figure S16. Amplifications of CDK6 and MET detected in the brain metastasis of case 138. Figure S17. Amplifications of CCNE1 and AKT2 detected in the brain metastasis of case 138. Figure S18. Amplification of EGFR detected in a regional lymph node from case 296. Figure S19. Power for somatic mutation detection in 86 matched primary-tumor and brain-metastasis samples. Figure S20. Calling of amplifications in primary-tumor samples and paired brain metastases.

Published
2023

31. Supplemental Table 1 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 1

Published
2023

32. Supplemental Figure 7 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S7

Published
2023

33. Supplemental Table 2 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 2

Published
2023

34. Supplemental Figure 10 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S10

Published
2023

35. Supplemental Table 5 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 5

Published
2023

36. Supplemental Table 7 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 7

Published
2023

37. Supplemental Table 4 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 4

Published
2023

38. Supplementary File 1 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Author

William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos

Abstract

Supplementary File 1. Power for detection of somatic point mutations in coding exons of TARGET genes. The description for the plots in Supplementary File 1 can be found in the Legend of Supplementary Figure S1.

Published
2023

39. Data from Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab

Author

Ian E. Krop, Eric P. Winer, Franziska Michor, Kornelia Polyak, Tari A. King, Leila Russo, Patrizia Dell'Orto, Aditya Bardia, Michelle K. DeMeo, Eileen Wrabel, Adrienne G. Waks, Laura M. Spring, Carlos L. Arteaga, Vandana G. Abramson, Ingrid A. Mayer, Denise A. Yardley, Lorenzo Trippa, Shayna Stein, Giuseppe Viale, and Otto Metzger Filho

Abstract

Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies.Significance:HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection.See related commentary by Okines and Turner, p. 2369.This article is highlighted in the In This Issue feature, p. 2355

Published
2023

40. Supplementary Tables 1 and 2 from Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial

Author

Jeffrey A. Meyerhardt, Charles S. Fuchs, Frank B. Hu, Pamela S. Douglas, Tara Sanft, Thomas A. Abrams, Kimmie Ng, Eric P. Winer, Sara M. Tolaney, Maura Harrigan, Brenda Cartmel, Alexandra Sorrentino, Michael N. Pollak, Nancy Campbell, Lee W. Jones, Melinda L. Irwin, Jennifer A. Ligibel, Sui Zhang, and Justin C. Brown

Abstract

Supplementary Tables 1 and 2

Published
2023

41. Supplemental Figure 3 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S3

Published
2023

42. Supplemental Figure 2 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S2

Published
2023

43. Supplementary File 3 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Author

William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos

Abstract

Supplementary File 3. Detailed plots of the data used for phylogenetic inference in each case. The description for the plots in Supplementary File 3 can be found in the Legend of Supplementary Figure S13-S17.

Published
2023

44. Supplementary Data from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplementary material

Published
2023

45. Supplementary File 2 from Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets

Author

William C. Hahn, Gad Getz, David N. Louis, José Baselga, Tracy T. Batchelor, Rameen Beroukhim, Eric S. Lander, Stacey Gabriel, Levi Garraway, Matthew Meyerson, Anat Stemmer-Rachamimov, Eric P. Winer, Nancy U. Lin, Michael S. Rabin, Carrie Sougnez, Sabina Signoretti, Toni K. Choueiri, Mai P. Hoang, Bruce E. Johnson, Aaron R. Thorner, Paul Van Hummelen, Corey M. Gill, Frederick G. Barker, Mara Rosenberg, Aaron Chevalier, Aaron McKenna, Sung-Hye Park, Sun Ha Paek, Ian F. Dunn, William T. Curry, Elena Martinez-Saez, Joan Seoane, Josep Tabernero, Keith L. Ligon, Kristian Cibulskis, Peleg M. Horowitz, Michael S. Lawrence, Eliezer M. Van Allen, Robert T. Jones, Amaro Taylor-Weiner, Daniel P. Cahill, Sandro Santagata, Scott L. Carter, and Priscilla K. Brastianos

Abstract

Supplementary File 2. Detailed plots of SCNA calls in TARGET genes. The description for the plots in Supplementary File 2 can be found in the Legend of Supplementary Figure S3.

Published
2023

46. Supplemental Figure 6 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Figure S6

Published
2023

47. Supplemental Table 8 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 8

Published
2023

48. Supplemental Table 3 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 3

Published
2023

49. Supplemental Table 6 from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer

Author

Nikhil Wagle, Sean G. Buchanan, Nancy U. Lin, Sara M. Tolaney, Eric P. Winer, Levi A. Garraway, Jill D. Kremer, Melissa E. Hughes, Gerald Batist, Quincy S. Chu, Gerard J. Oakley, Patricia S. Smith, John R. Stille, Valerie M. Jansen, Chunping Yu, Xiang S. Ye, Lacey M. Litchfield, Ricardo Martinez, Stephen H. Parsons, Adrienne G. Waks, Utthara Nayar, Kailey J. Kowalski, Karla Helvie, Pingping Mao, Flora Luo, Dewey Kim, Maxwell R. Lloyd, Jorge E. Buendia-Buendia, Gabriela N. Johnson, Xueqian Gong, Ofir Cohen, and Seth A. Wander

Abstract

Supplemental Table 6

Published
2023

50. Supplementary Figure from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

Author

Gerburg M. Wulf, Peter J. Park, Hans P. Eikesdal, Helen Won, David B. Solit, Panagiotis A. Konstantinopoulos, Ursula A. Matulonis, Per E. Lønning, Stian Knappskog, Erica L. Mayer, Eric P. Winer, Nadine M. Tung, Nabihah Tayob, Niya Xiong, Madeline Polak, Antuan Tran, Victor Mao, Doga C. Gulhan, and Felipe Batalini

Abstract

Supplementary Figure from Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

Published
2023

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