Publications by authors named "Chau Dang"

96 Publications

Chemotherapy-related amenorrhea (CRA) after adjuvant ado-trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT Trial).

Breast Cancer Res Treat 2021 Aug 12;189(1):103-110. Epub 2021 Jun 12.

Lowell General Hospital, Lowell, USA.

Purpose: Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1).

Methods: Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6-12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis.

Results: Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23-53) among 18 who had received TH and 46 (range 34-54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045).

Conclusion: Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens.
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http://dx.doi.org/10.1007/s10549-021-06267-8DOI Listing
August 2021

Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial.

J Clin Oncol 2021 Jul 2;39(21):2375-2385. Epub 2021 Jun 2.

Abramsom Cancer Center, University of Pennsylvania, Philadelphia, PA.

Purpose: The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC).

Methods: Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1.

Results: The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH.

Conclusion: Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.
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http://dx.doi.org/10.1200/JCO.20.03398DOI Listing
July 2021

NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.

J Natl Compr Canc Netw 2021 05 1;19(5):484-493. Epub 2021 May 1.

26Research Advocacy Network.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.
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http://dx.doi.org/10.6004/jnccn.2021.0023DOI Listing
May 2021

Racial and Socioeconomic Disparities in Cardiotoxicity Among Women With HER2-Positive Breast Cancer.

Am J Cardiol 2021 05 20;147:116-121. Epub 2021 Feb 20.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York. Electronic address:

Breast cancer and cardiovascular-specific mortality are higher among blacks compared with whites, but disparities in cancer therapy-related adverse cardiovascular outcomes have not been well studied. We assessed for the contribution of race and socioeconomic status on cardiotoxicity among women with HER2-positive breast cancer. This retrospective cohort analysis studied women diagnosed with stage I-III HER2-positive breast cancer from 2004-2013. All underwent left ventricular ejection fraction assessment at baseline and at least one follow-up after beginning trastuzumab. Multivariable logistic regression was used to assess the association between race and socioeconomic status (SES) on cardiotoxicity, defined by clinical heart failure (New York Heart Association class III or IV) or asymptomatic left ventricular ejection fraction decline (absolute decrease ≥ 10% to < 53%, or ≥ 16%). Blacks had the highest prevalence of hypertension, diabetes, and increased BMI. Neighborhood-level SES measures including household income and educational attainment were lower for blacks compared with whites and others. The unadjusted cardiotoxicity risk was significantly higher in black compared with white women (OR, 2.10; 95% CI, 1.42 to 3.10). In a multivariable analysis, this disparity persisted after controlling for relevant cardiovascular risk factors (adjusted OR, 1.88; 95% CI, 1.25 to 2.84). Additional models adjusting for SES factors of income, educational attainment, and insurance status did not significantly alter the association between race and cardiotoxicity. In conclusion, black women are at increased risk of cardiotoxicity during HER2-targeted breast cancer therapy. Future etiologic analyses, particularly studies exploring biologic or genetic mechanisms, are needed to further elucidate and reduce racial disparities in cardiotoxicity.
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http://dx.doi.org/10.1016/j.amjcard.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076074PMC
May 2021

Long-term follow-up assessment of cardiac safety in SAFE-HEaRt, a clinical trial evaluating the use of HER2-targeted therapies in patients with breast cancer and compromised heart function.

Breast Cancer Res Treat 2021 Feb 5;185(3):863-868. Epub 2021 Jan 5.

Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington DC, USA.

Purpose: HER2-targeted therapies are associated with cardiotoxicity which is usually asymptomatic and reversible. We report the updated cardiac safety assessment of patients with compromised heart function receiving HER2-targeted therapy for breast cancer, enrolled in the SAFE-HEaRt trial, at a median follow-up of 3.5 years.

Methods: Thirty patients with stage I-IV HER2-positive breast cancer receiving trastuzumab with or without pertuzumab, or ado-trastuzumab emtansine (T-DM1), with asymptomatic LVEF (left ventricular ejection fraction) 40-49%, were started on cardioprotective medications, with the primary endpoint being completion of HER2-targeted therapy without cardiac events (CE) or protocol-defined asymptomatic worsening of LVEF. IRB-approved follow-up assessment included 23 patients.

Results: Median follow-up as of June 2020 is 42 months. The study met its primary endpoint with 27 patients (90%) completing their HER2-targeted therapies without cardiac issues. Of the 23 evaluable patients at long-term f/u, 14 had early stage breast cancer, and 9 had metastatic disease, 8 of whom remained on HER2-targeted therapies. One patient developed symptomatic heart failure with no change in LVEF. There were no cardiac deaths. The mean LVEF improved to 52.1% from 44.9% at study baseline, including patients who remained on HER2-targeted therapy, and those who received prior anthracyclines.

Conclusions: Long-term follow-up of the SAFE-HEaRt study continues to provide safety data of HER2-targeted therapy use in patients with compromised heart function. The late development of cardiac dysfunction is uncommon and continued multi-disciplinary oncologic and cardiac care of patients is vital for improved patient outcomes.
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http://dx.doi.org/10.1007/s10549-020-06053-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207895PMC
February 2021

Cardiotoxicity Surveillance and Risk of Heart Failure During HER2 Targeted Therapy.

JACC CardioOncol 2020 Jun 16;2(2):166-175. Epub 2020 Jun 16.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Guidelines recommend left ventricular ejection fraction (LVEF) assessments every 3 months for cardiotoxicity monitoring during human epidermal growth factor receptor 2 (HER2) targeted therapy. Evidence in support of this practice is lacking.

Objectives: This study examines the association between adherence to cardiotoxicity surveillance guidelines and heart failure (HF) in HER2-positive breast cancer patients.

Methods: A case-control study was performed in 53 patients who developed cardiotoxicity during HER2 targeted therapy, and 159 controls matched by age, anthracycline exposure, and year of treatment. Cardiotoxicity was defined as HF (New York Heart Association functional class III or IV) or cardiac death. Adherence to cardiotoxicity surveillance guidelines was ascertained from the beginning of HER2 targeted therapy to the diagnosis date of HF for cases or the corresponding timepoint for matched controls. Conditional logistic regression was used for case-control comparisons.

Results: Eighty-one percent of cases and controls were previously treated with an anthracycline. Adherence to cardiotoxicity surveillance guidelines during the entire observation period or during the first 6 months of treatment was not associated with lower risk of HF. An LVEF <55% at any surveillance timepoint was identified in 49% of cases and 3% of controls, and an LVEF <55% during the final surveillance timepoint before developing HF was identified in 54% of cases and 4% of controls. In multivariable-adjusted analyses, LVEF <55% at any timepoint or during the final surveillance timepoint (odds ratio: 27.0; 95% confidence interval: 9.3 to 78.8 and odds ratio: 25.6; 95% confidence interval: 7.3 to 90.3, respectively) was associated with HF.

Conclusions: Patients with LVEF <55% on routine surveillance during HER2 targeted therapy are at increased risk for HF. Additional studies to define their optimal management are warranted.
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http://dx.doi.org/10.1016/j.jaccao.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584138PMC
June 2020

Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.

J Clin Oncol 2020 12 23;38(35):4184-4193. Epub 2020 Oct 23.

Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, NC.

Purpose: CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.

Patients And Methods: Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.

Results: One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.

Conclusion: In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
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http://dx.doi.org/10.1200/JCO.20.01276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723687PMC
December 2020

InSight Care Pilot Program: Redefining Seeing a Patient.

JCO Oncol Pract 2020 10 29;16(10):e1050-e1059. Epub 2020 May 29.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Early detection and management of symptoms in patients with cancer improves outcomes. However, the optimal approach to symptom monitoring and management is unknown. InSight Care is a mobile health intervention that captures symptom data and facilitates patient-provider communication to mitigate symptom escalation.

Patients And Methods: Patients initiating antineoplastic treatment at a Memorial Sloan Kettering regional location were eligible. Technology supporting the program included the following: a predictive model that identified patient risk for a potentially preventable acute care visit; a secure patient portal enabling communication, televisits, and daily delivery of patient symptom assessments; alerts for concerning symptoms; and a symptom-trending application. The main outcomes of the pilot were feasibility and acceptability evaluated through enrollment and response rates and symptom alerts, and perceived value evaluated on the basis of qualitative patient and provider interviews.

Results: The pilot program enrolled 100 high-risk patients with solid tumors and lymphoma (29% of new treatment starts goal of 25%). Over 6 months of follow-up, the daily symptom assessment response rate was 56% (the goal was 50%), and 93% of patients generated a severe symptom alert. Patients and providers perceived value in the program, and archetypes were developed for program improvement. Enrolled patients were less likely to use acute care than were other high-risk patients.

Conclusion: InSight Care was feasible and holds the potential to improve patient care and decrease facility-based care. Future work should focus on optimizing the cadence of patient assessments, the workforce supporting remote symptom management, and the return of symptom data to patients and clinical teams.
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http://dx.doi.org/10.1200/OP.20.00214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564136PMC
October 2020

Trastuzumab: Weighing the Benefits and the Risks.

J Natl Cancer Inst 2020 12;112(12):1181-1182

Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

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http://dx.doi.org/10.1093/jnci/djaa055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824039PMC
December 2020

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 04;18(4):452-478

O'Neal Comprehensive Cancer Center at UAB.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.
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http://dx.doi.org/10.6004/jnccn.2020.0016DOI Listing
April 2020

Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer: A Randomized Controlled Trial.

Circulation 2020 02 17;141(7):560-570. Epub 2020 Feb 17.

Memorial Sloan Kettering Cancer Center, New York, NY (J.M.S., C.T.D., A.F.Y., D.C., C.C., C.C., M.G.M., L.W.J.).

Background: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer.

Methods: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VOpeak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VOpeak (mL O·kg·min) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety.

Results: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VOpeak increased 0.6±1.7 mL O·kg·min (=0.05) and 0.8±1.8 mL O·kg·min (=0.07) in LET and NLET, respectively, compared with attention control. Change in VOpeak ranged from -2.7 to 4.1 mL O·kg·min and from -3.6 to 5.1 mL O·kg·min in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VOpeak responders (ie, Δ ≥1.32 mL O·kg·min). NLET improved all patient-reported outcomes compared with attention control.

Conclusions: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032604PMC
February 2020

Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer.

JAMA Cardiol 2020 03;5(3):309-317

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer.

Objective: To determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer.

Design, Setting, And Participants: This cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019.

Main Outcomes And Measures: Speckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2).

Results: A total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (β coefficient, -0.75; 95% CI, -1.32 to -0.18).

Conclusions And Relevance: Treatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.
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http://dx.doi.org/10.1001/jamacardio.2019.5586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990842PMC
March 2020

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial.

JAMA Netw Open 2019 11 1;2(11):e1916211. Epub 2019 Nov 1.

Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown.

Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer.

Design, Setting, And Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019.

Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks.

Main Outcomes And Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival.

Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction.

Conclusions And Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit.

Trial Registration: ClinicalTrials.gov identifier: NCT02252887.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.16211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902832PMC
November 2019

Impact of the 2018 American Society of Clinical Oncology/College of American Pathologists HER2 Guideline Updates on HER2 Assessment in Breast Cancer With Equivocal HER2 Immunohistochemistry Results With Focus on Cases With /CEP17 Ratio <2.0 and Average Copy Number ≥4.0 and <6.0.

Arch Pathol Lab Med 2020 05 24;144(5):597-601. Epub 2019 Oct 24.

From the Departments of Pathology (Drs Hoda, Brogi, Xu, Ross, and Wen and Ms Ventura), Medicine (Drs Dang, Robson, and Norton), and Surgery (Dr Morrow), Memorial Sloan Kettering Cancer Center, New York, New York.

Context.—: The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline.

Objective.—: To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results.

Design.—: We retrospectively reviewed fluorescence in situ hybridization (FISH) data (/CEP17 ratio and average copy number per cell) of HER2 immunohistochemistry-equivocal (2+ or 1+ to 2+) breast cancers at our center between January 2014 and May 2018 and compared FISH results according to 2013 and 2018 guidelines.

Results.—: A total of 1666 FISH results from 1421 patients with equivocal HER2 immunohistochemistry were reviewed. Based on the 2013 guideline, FISH results were amplified in 346 cases (20.8%), equivocal in 242 (14.5%), and nonamplified in 1078 (64.7%). Using the 2018 guideline, 258 cases (16%) were reclassified, including 242 previously equivocal test results (15%) and 16 previously positive results (1%) reclassified as negative. The subset of 2013 HER2-equivocal and 2018 HER2-nonamplified cases with /CEP17 ratio lower than 2.0 and average copy number 4.0 or higher and lower than 6.0 showed higher incidence of micropapillary morphology compared with HER2-amplified cases. Despite most patients in this group not receiving HER2-targeted treatment, 96% had no evidence of disease at follow-up.

Conclusions.—: The 2018 guideline eliminated FISH-equivocal cases by reclassifying HER2-equivocal cases and cases with nonclassical amplification without HER2 overexpression as HER2 negative. As a consequence, we observed a considerable increase in FISH-negative cases and a slight decrease in FISH-positive cases.
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http://dx.doi.org/10.5858/arpa.2019-0307-OADOI Listing
May 2020

Trastuzumab Cures Cancer and Disrupts the Practice of Cardiology.

JACC CardioOncol 2019 Sep 4;1(1):11-13. Epub 2019 Jul 4.

Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York, USA.

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http://dx.doi.org/10.1016/j.jaccao.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352217PMC
September 2019

Pathologic complete response rate according to HER2 detection methods in HER2-positive breast cancer treated with neoadjuvant systemic therapy.

Breast Cancer Res Treat 2019 Aug 29;177(1):61-66. Epub 2019 May 29.

Department of Pathology, Memorial Sloan Kettering Cancer, 1275 York Avenue, New York, NY, 10065, USA.

Purpose: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are known to have significant clinical and pathological response to neoadjuvant systemic therapy (NST). The aim of this study was to identify factors associated with pathological complete response (pCR), defined as no residual invasive carcinoma in the breast and axillary lymph nodes (ypT0/is ypN0), among patients with HER2-positive breast cancer and to compare pCR rates between breast cancers with HER2 protein overexpression by immunohistochemistry (IHC) versus HER2 gene amplification by fluorescence in situ hybridization (FISH) in the absence of protein overexpression by IHC.

Methods: We conducted a retrospective review of HER2-positive breast cancer patients treated with NST and surgery at Memorial Sloan Kettering Cancer Center between January 2013 and May 2018. Estrogen receptor (ER), progesterone receptor (PR), and HER2 status were assessed according to the 2018 ASCO/CAP guidelines.

Results: During the study period, 560 patients were identified. Of 531 patients with IHC results available, 455 patients had HER2 IHC 3+, and 76 had IHC < 3+ but HER2 amplification detected by FISH. The overall pCR rate was 59% (330/560). The pCR rate among patients with HER2 protein overexpression (IHC 3+) was 67%, compared to 17% among patients with HER2 amplification by FISH (IHC < 3+). On univariate and multivariate analyses, HER2 protein overexpression by IHC (IHC 3+) was a significant predictor of pCR, along with grade 3 histology, PR-negative status, and dual anti-HER2 therapy.

Conclusion: Although both HER2 IHC and FISH are standard HER2 testing methods in breast cancer, achievement of pCR is associated with HER2 IHC expression level, among other factors.
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http://dx.doi.org/10.1007/s10549-019-05295-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640097PMC
August 2019

Local-regional recurrence in women with small node-negative, HER2-positive breast cancer: results from a prospective multi-institutional study (the APT trial).

Breast Cancer Res Treat 2019 Jul 19;176(2):303-310. Epub 2019 Apr 19.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T).

Methods: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method.

Results: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8).

Conclusion: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.
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http://dx.doi.org/10.1007/s10549-019-05238-4DOI Listing
July 2019

Seven-Year Follow-Up Analysis of Adjuvant Paclitaxel and Trastuzumab Trial for Node-Negative, Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer.

J Clin Oncol 2019 08 2;37(22):1868-1875. Epub 2019 Apr 2.

1Dana-Farber Cancer Institute, Boston, MA.

Purpose: The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN).

Patients And Methods: In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer-specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN.

Results: A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, , associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%).

Conclusion: With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.
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http://dx.doi.org/10.1200/JCO.19.00066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587424PMC
August 2019

Assessment of Early Radiation-Induced Changes in Left Ventricular Function by Myocardial Strain Imaging After Breast Radiation Therapy.

J Am Soc Echocardiogr 2019 04 28;32(4):521-528. Epub 2019 Feb 28.

Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York.

Background: Radiation therapy (RT)-induced cardiotoxicity is among the concerning sequelae of breast cancer (BCA) treatment, particularly in HER2-positive BCA patients who receive anthracyclines and trastuzumab-based therapy. The aim of this study was to assess for early RT-induced changes in echocardiographic and circulating biomarkers of left ventricular (LV) function and evaluate their association with radiation dose to the heart among patients with HER2-positive BCA treated with contemporary RT.

Methods: A total of 47 women with HER2-positive BCA who were treated with an anthracycline, trastuzumab, and RT to the breast and/or chest wall ± regional lymph nodes were included in this study. Two-dimensional echocardiography with speckle-tracking imaging was performed at baseline (prechemotherapy), prior to and after RT (pre-RT and post-RT), and 6 months post-RT. High-sensitivity troponin I (hsTnI) was measured pre-RT and post-RT. Associations between mean heart dose (MHD) and changes in LV function after RT were examined in multivariable linear regression models.

Results: The MHD was 1.8 ± 1.5 Gy for patients receiving left-sided RT (n = 26) and 1.1 ± 1.3 Gy for patients receiving right-sided RT (n = 21). Pre-RT, post-RT, and 6-month post-RT echocardiograms were performed at median (interquartile range) of 49 days (27, 77) before and 54 days (25, 78) and 195 days (175, 226) after RT, respectively. Compared with pre-RT, a minimal decrease in LV ejection fraction was observed post-RT (61% ± 7% vs 59% ± 8%; P = .003) without any significant change in global longitudinal, circumferential, or radial strain or diastolic indices at the post-RT timepoint. Median (interquartile range) concentrations of hsTnI decreased from 5.7 pg/mL (3.0, 8.7) pre-RT to 3.7 pg/mL (2.0, 5.9) post-RT. There was no significant change in systolic or diastolic indices of LV function at 6 months post-RT compared with pre-RT. MHD was not associated with changes in echocardiographic parameters of LV function after RT.

Conclusions: Breast RT using contemporary techniques can be delivered without evidence of early subclinical LV dysfunction or injury as measured by echocardiography and hsTnI in patients treated with anthracyclines and trastuzumab. Future studies should focus on identifying alternative biomarkers to elucidate early RT-induced cardiovascular effects and further characterizing long-term cardiovascular outcomes associated with contemporary breast RT.
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http://dx.doi.org/10.1016/j.echo.2018.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487646PMC
April 2019

NCCN Guidelines Insights: Breast Cancer, Version 3.2018.

J Natl Compr Canc Netw 2019 02;17(2):118-126

26Huntsman Cancer Institute at the University of Utah.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.
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http://dx.doi.org/10.6004/jnccn.2019.0009DOI Listing
February 2019

Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction.

Breast Cancer Res Treat 2019 May 5;175(1):239-246. Epub 2019 Feb 5.

Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

Purpose: Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline.

Methods: Patients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III-IV) or cardiovascular death.

Results: Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25-42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29).

Conclusion: Continuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.
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http://dx.doi.org/10.1007/s10549-019-05139-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494676PMC
May 2019

Phase II Study of Weekly Paclitaxel with Trastuzumab and Pertuzumab in Patients with Human Epidermal Growth Receptor 2 Overexpressing Metastatic Breast Cancer: 5-Year Follow-up.

Oncologist 2019 08 2;24(8):e646-e652. Epub 2019 Jan 2.

Memorial Sloan-Kettering Cancer Center, New York New York, USA.

Background: Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up.

Materials And Methods: In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS.

Results: From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns.

Conclusion: With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached.

Implications For Practice: The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.
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http://dx.doi.org/10.1634/theoncologist.2018-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693713PMC
August 2019

The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers.

Cancer Cell 2018 09;34(3):427-438.e6

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.
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http://dx.doi.org/10.1016/j.ccell.2018.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327853PMC
September 2018

Risk-Imaging Mismatch: Why Is There a Disconnect?

J Clin Oncol 2018 10 31;36(30):2975-2977. Epub 2018 Aug 31.

Chau T. Dang, Anthony F. Yu, Jennifer Liu, and Richard Steingart, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1200/JCO.2018.78.9354DOI Listing
October 2018

In Reply.

Oncologist 2018 12 17;23(12):e165-e166. Epub 2018 Aug 17.

Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

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http://dx.doi.org/10.1634/theoncologist.2018-0101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292538PMC
December 2018

Overview of Breast Cancer Therapy.

PET Clin 2018 Jul;13(3):339-354

Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, USA. Electronic address:

Breast cancer treatment is multidisciplinary. Most women with early stage breast cancer are candidates for breast-conserving surgery with radiotherapy or mastectomy. The risk of local recurrence and the chance of survival does not differ with these approaches. Sentinel node biopsy is used for axillary staging, and individualized approaches are minimizing the need for axillary dissection in women with positive sentinel nodes. Adjuvant systemic therapy is used in most women based on proven survival benefit, and molecular profiling to individualize treatment based on risk is now a clinical reality for patients with hormone receptor-positive cancers.
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http://dx.doi.org/10.1016/j.cpet.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092031PMC
July 2018

Left Ventricular Ejection Fraction Monitoring Adherence Rates: Why So Low?

JACC Cardiovasc Imaging 2018 08;11(8):1094-1097

Division of Medical Oncology, Department of Medicine, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1016/j.jcmg.2018.02.027DOI Listing
August 2018

Association of Circulating Tumor Cells With Late Recurrence of Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Oncol 2018 12;4(12):1700-1706

Department of Medicine, Division of Hematology/Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis.

Importance: Late recurrence 5 or more years after diagnosis accounts for at least one-half of all cases of recurrent hormone receptor-positive breast cancer.

Objective: To determine whether the presence of circulating tumor cells (CTCs) in a peripheral blood sample obtained approximately 5 years after diagnosis was associated with late clinical recurrence of operable human epidermal growth factor receptor 2-negative breast cancer.

Design, Setting, And Participants: This per-protocol secondary analysis of the Double-Blind Phase III Trial of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With Bevacizumab or Placebo in Patients With Lymph Node Positive and High Risk Lymph Node Negative Breast Cancer enrolled patients from 2007 to 2011 who were without clinical evidence of recurrence between 4.5 and 7.5 years after primary surgical treatment of human epidermal growth factor receptor 2-negative stage II-III breast cancer followed by adjuvant systemic therapy. Patients were enrolled in a subprotocol for secondary analysis from February 25, 2013, to July 29, 2016, after signing consent for the subprotocol. The analysis was performed in April 2018.

Interventions: A blood sample was obtained for identification and enumeration of CTCs.

Main Outcome And Measures: The association between a positive CTC assay result (at least 1 CTC per 7.5 mL of blood) and clinical recurrence.

Results: Among 547 women included in this analysis, the results of the CTC assay were positive for 18 of 353 with hormone receptor-positive disease (5.1% [95% CI, 3.0%-7.9%]); 23 of 353 patients (6.5% [95% CI, 4.2%-9.6%]) had a clinical recurrence. The recurrence rates per person-year of follow-up in the CTC-positive and CTC-negative groups were 21.4% (7 recurrences per 32.7 person-years) and 2.0% (16 recurrences per 796.3 person-years), respectively. In multivariate models including clinical covariates, a positive CTC assay result was associated with a 13.1-fold higher risk of recurrence (hazard ratio point estimate, 13.1; 95% CI, 4.7-36.3). Seven of 23 patients (30.4% [95% CI, 13.2%-52.9%]) with recurrence had a positive CTC assay result at a median of 2.8 years (range, 0.1-2.8 years) before clinical recurrence. The CTC assay result was also positive for 8 of 193 patients (4.1% [95% CI, 1.8%-8.0%]) with hormone receptor-negative disease, although only 1 patient (0.5% [95% CI, 0%-2.9%]) experienced disease recurrence (this patient was CTC negative).

Conclusions And Relevance: A single positive CTC assay result 5 years after diagnosis of hormone receptor-positive breast cancer provided independent prognostic information for late clinical recurrence, which provides proof of concept that liquid-based biomarkers may be used to risk stratify for late recurrence and guide therapy.

Trial Registration: ClinicalTrials.gov identifier: NCT00433511.
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http://dx.doi.org/10.1001/jamaoncol.2018.2574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385891PMC
December 2018

Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103).

J Clin Oncol 2018 09 24;36(25):2621-2629. Epub 2018 Jul 24.

Kathy D. Miller, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Anne O'Neill, Dana-Farber Cancer Institute, Boston, MA; William Gradishar, Northwestern University, Chicago; Nguyet Anh Le-Lindqwister, Heartland Cancer Research National Cancer Institute Community Oncology Research Program, Peoria, IL; Timothy J. Hobday, Mayo Clinic, Rochester; Stuart Bloom, Abbott Northwestern Hospital, Minneapolis, MN; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia; Adam M. Brufsky, University of Pittsburgh, Pittsburgh, PA; Ingrid A. Mayer, Vanderbilt University, Nashville, TN; Amye J. Tevaarwerk, University of Wisconsin, Madison, WI; Joseph A. Sparano, Montefiore Hospital and Medical Center, Bronx; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Carolyn B. Hendricks, Association Community Clinical Oncology Program, Bethesda, MD; Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ; and George W. Sledge JR, Stanford University, Stanford, CA.

Purpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.
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http://dx.doi.org/10.1200/JCO.2018.79.2028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118403PMC
September 2018
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