Publications by authors named "Aditya Bardia"

142 Publications

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.

Cancer Discov 2021 May 3. Epub 2021 May 3.

Medical Oncology, Dana-Farber Cancer Institute

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 2 locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in > 5% but < 50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the non-heterogenous subgroup and 0% in the heterogenous group (p<0.0001, adjusted for hormone receptor status). Single cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 non-amplified 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.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1557DOI Listing
May 2021

Temporal trends in inpatient oncology census before and during the COVID-19 pandemic and rates of nosocomial COVID-19 among patients with cancer at a large academic center.

Oncologist 2021 May 1. Epub 2021 May 1.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: The Coronavirus Disease-2019 (COVID-19) pandemic has significantly impacted healthcare systems. However, to date, the trend of hospitalizations in the oncology patient population has not been studied and the frequency of nosocomial spread to cancer patients is not well-understood. The objectives of this study were to evaluate the impact of COVID-19 on inpatient oncology census and determine the nosocomial rate of COVID-19 in cancer patients admitted at a large academic center.

Materials And Methods: Medical records of cancer patients diagnosed with COVID-19 and admitted were reviewed to evaluate the temporal trends in inpatient oncology census during pre-COVID (Jan 2019-Feb 2020), COVID (March-May 2020), and post-COVID surge (June-August 2020) in the region. In addition, nosocomial infection rates of SARS-CoV-2 were reviewed.

Results: Overall, the daily inpatient census was steady in 2019 (median=103; range:92-118) and until February 2020 (median=112; range:102-114). However, there was a major decline from March to May 2020 (median=68; range:57-104), with 45.4% lower admissions during April 2020. As the COVID surge eased, the daily inpatient census over time returned to the pre-COVID baseline (median=103; range:99-111). One patient (1/231, 0.004%) had SARS-CoV-2 positive test 13 days after hospitalization and it is unclear if it was nosocomial or community spread.

Conclusion: In this study, inpatient oncology admissions decreased substantially during the COVID surge, but over time returned to the pre-COVID baseline. With aggressive infection control measures, the rates of nosocomial transmission were exceedingly low and should provide reassurance to those seeking medical care, including inpatient admissions when medically necessary.

Implications For Practice: The COVID-19 pandemic has had a major impact on the healthcare system, and cancer patients are a vulnerable population. As a result of the urgent need for inpatient capacity, non-COVID care has been deferred or delayed. In our study, we observe a drastic decline in the daily inpatient oncology census from March to May 2020 compared to the same time frame in the previous year. We investigate reasons for this decline. The concern is that some patients and providers may be deferring admission because of fear of the individual acquiring COVID in the hospital. However, we analyzed the nosocomial rate of COVID infection in admitted cancer patients to our center confirming that none of the patients in this study acquired the infection while hospitalized. These findings suggest that aggressive infection control measures can help mitigate the nosocomial infection risk among cancer patients and that the inpatient setting is a safe environment, providing reassurance to those seeking medical care.
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http://dx.doi.org/10.1002/onco.13807DOI Listing
May 2021

Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

N Engl J Med 2021 04;384(16):1529-1541

From the Division of Medical Oncology, Massachusetts General Hospital Cancer Center (A. Bardia), and the Department of Medical Oncology, Dana-Farber Cancer Institute (S.M.T.) - both in Boston; the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H.); the Medical Oncology Department and the Department of Drug Development and Innovation, Institut Curie, Paris (D.L.), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (F.D.), and the Department of Medical Oncology, Centre Eugène Marquis, Rennes (V.D.) - all in France; the Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven (K.P.), and the Clinical Trials Conduct Unit (P.A.), Institut Jules Bordet-Université Libre de Bruxelles (M.J.P.), Brussels - all in Belgium; the Medical Oncology Department and Breast Cancer Group, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (M.O.), and the International Breast Cancer Center, Quiron Group (J.C.) - all in Barcelona; Magee-Womens Hospital and the Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (A. Brufsky); Ohio State University Wexner Medical Center, Columbus (S.D.S.); Columbia University Irving Medical Center (K.K.) and Memorial Sloan Kettering Cancer Center (T.T.) - both in New York; Northside Hospital, Atlanta (A.B.Z.); Florida Cancer Specialists, Tampa (R.W.); Georgetown Lombardi Comprehensive Cancer Center, Washington, DC (F.L.); Rocky Mountain Cancer Centers, Greenwood Village, CO (S.D.); Baylor University Medical Center and Texas Oncology, Dallas (J.O.); Segal Cancer Centre, Jewish General Hospital, Montreal (C.F.); Barts Cancer Institute, Queen Mary University of London, London (P.S.); University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (L.A.C.); Gianni Bonadonna Foundation, Milan (L.G.); the Department of Medicine and Research, Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, Frankfurt, Germany (S.L.); Immunomedics, Morris Plains, NJ (D.M.G., Q.H., M.S.O., L.M.I.); and the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.).

Background: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker.

Methods: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases.

Results: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment.

Conclusions: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).
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http://dx.doi.org/10.1056/NEJMoa2028485DOI Listing
April 2021

Impact of cancer history on outcomes among hospitalized COVID-19 patients.

Oncologist 2021 Apr 15. Epub 2021 Apr 15.

Dana-Farber Cancer Institute, Boston, MA.

Background: Early reports suggested increased mortality from COVID-19 in patients with cancer but lacked rigorous comparisons to non-cancer patients. We investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death in hospitalized COVID-19 patients.

Patients And Methods: We identified patients with a history of cancer admitted to 2 large hospitals between 3/13/2020 and 5/10/2020 with laboratory-confirmed COVID-19 and matched them 1:2 to patients without a history of cancer.

Results: 56.2% of the population was male, with a median age of 69 years (range: 30-96). The median time since cancer diagnosis was 35.6 months (range 0.39-435); 80% had a solid tumor and 20% had a hematologic malignancy. Among patients with cancer, 27.8% died or entered hospice vs. 25.6% among patients without cancer. In multivariable analyses, the odds of death/hospice were similar (OR: 1.09, 95%CI: 0.65-1.82). The odds of intubation (OR: 0.46, 95%CI: 0.28-0.78), shock (OR: 0.54, 95%CI: 0.32-0.91), and intensive care unit admission (OR: 0.51, 95%CI: 0.32-0.81) were lower for patients with a history of cancer vs. controls. Patients with active cancer or who had received cancer-directed therapy in the past 6 months had similar odds of death/hospice compared to cancer survivors (univariable OR: 1.31, 95%CI: 0.66-2.60; multivariable OR: 1.47, 95%CI: 0.69-3.16).

Conclusions: Patients with a history of cancer hospitalized for COVID-19 had similar mortality to matched hospitalized COVID-19-positive patients without cancer, and a lower risk of complications. In this population, patients with active cancer or recent cancer treatment had a similar risk for adverse outcomes compared to cancer survivors.

Implications For Practice: An understanding of the comorbidities and patient characteristics that portend a severe outcome from COVID-19 can improve patient care and guide the utilization of scare resources. To develop this understanding, we investigated whether a current cancer diagnosis or cancer history is an independent risk factor for death or hospice admission in hospitalized COVID-19 patients. We found that active cancer, systemic cancer therapy, and a history of cancer are not independent risk factors for death from COVID-19 among hospitalized patients, and hospitalized patients without cancer are more likely to have severe COVID-19 marked by intubation, ICU admission, ARDS, and shock. These findings provide reassurance to cancer survivors and patients as to their relative risk of severe COVID-19, may encourage oncologists to provide standard anti-cancer therapy in patients at risk of COVID-19, and guide triage in future waves of infection.
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http://dx.doi.org/10.1002/onco.13794DOI Listing
April 2021

Highlights in metastatic breast cancer from the European Society for Medical Oncology Virtual Congress 2020: commentary.

Authors:
Aditya Bardia

Clin Adv Hematol Oncol 2020 Nov;18 Suppl 17(11):20-23

Harvard Medical School, Boston, Massachusetts.

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November 2020

Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.

J Natl Compr Canc Netw 2021 Mar 24:1-8. Epub 2021 Mar 24.

1Massachusetts General Hospital Cancer Center, and.

Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i.

Patients And Methods: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers.

Results: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib.

Conclusions: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.
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http://dx.doi.org/10.6004/jnccn.2020.7662DOI Listing
March 2021

Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR+/HER2- advanced breast cancer after progression on CDK4/6 inhibitors (TRINITI-1).

Clin Cancer Res 2021 Mar 15. Epub 2021 Mar 15.

Breast Medical Oncolohy, The University of Texas MD Anderson Cancer Center.

PURPOSE Standard-of-care treatment for metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i which has recently demonstrated significant OS benefit in 2 phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2- advanced breast cancer (ABC) after progression on a CDK4/6i. METHODS This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2- BC. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. RESULTS Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1-28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% CI, 31.1%-51.6%), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. CONCLUSION Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ETrefractory HR+/HER2- ABC after progression on a CDK4/6i.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2114DOI Listing
March 2021

Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018.

Oncologist 2021 Mar 3. Epub 2021 Mar 3.

Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death.

Methods: Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected.

Results: In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality.

Conclusion: This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality.

Implications For Practice:  The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.
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http://dx.doi.org/10.1002/onco.13740DOI Listing
March 2021

Clinical application of liquid biopsies to detect somatic mutations and guide potential therapeutic intervention for patients with metastatic breast cancer.

Oncotarget 2021 Jan 19;12(2):63-65. Epub 2021 Jan 19.

Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Plasma based genotyping via cell-free DNA may identify actionable mutations for potential therapeutic intervention in patients with advanced malignancies including breast cancer. In this article, we discuss recent studies using cell-free DNA testing to identify and classify somatic mutations in metastatic breast cancer, and potential future applications for the treatment of metastatic breast cancer.
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http://dx.doi.org/10.18632/oncotarget.27863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825638PMC
January 2021

Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.

J Clin Oncol 2021 Apr 29;39(12):1360-1370. Epub 2021 Jan 29.

University of Colorado, Aurora, CO.

Purpose: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha () mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D).

Methods: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability.

Results: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in mutant allele fraction.

Conclusion: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.
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http://dx.doi.org/10.1200/JCO.20.02272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078341PMC
April 2021

Tumor tissue- versus plasma-based genotyping for selection of matched therapy and impact on clinical outcomes in patients with metastatic breast cancer.

Clin Cancer Res 2021 Jan 27. Epub 2021 Jan 27.

Massachusetts General Hospital Cancer Center.

Purpose: Actionable mutations can guide genotype-directed matched therapy. We evaluated the utility of tissue-based and plasma-based genotyping for the identification of actionable mutations and selection of matched therapy in patients with metastatic breast cancer (MBC).

Methods: Patients with MBC who underwent tissue genotyping (institutional platform, 91 gene assay) or plasma based cell-free DNA (cfDNA, Guardant360, 73 gene assay) between January 2016 and December 2017 were included. A chart review of records to identify subtype, demographics, treatment, outcomes, and tissue genotyping or cfDNA results was performed. The incidence of actionable mutationsand the selection of matched therapy in tissue genotyping or cfDNA cohorts was determined. The impact of matched therapy status on overall survival (OS) in tissue genotyping or cfDNA subgroups was determined with Cox regression analysis.

Results: Of 252 patients who underwent cfDNA testing, 232 (92%) had detectable mutations, 196 (78%) had actionable mutations, and 86 (34%) received matched therapy. Of 118 patients who underwent tissue genotyping, 90 (76%) had detectable mutations, 59 (50%) had actionable mutations, and 13 (11%) received matched therapy. For cfDNA patients with actionable mutations, matched versus non-matched therapy was associated with better OS (HR 0.41, 95% CI: 0.23-0.73, p=0.002), and this remained significant in a multivariable analysis correcting for age, subtype, visceral metastases, and brain metastases (HR = 0.46, 95% CI: 0.26-0.83, p = 0.010).

Conclusion: Plasma-based genotyping identified high rates of actionable mutations, which was associated with significant application of matched therapy and better OS in patients with MBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3444DOI Listing
January 2021

A closer look at sacituzumab govitecan-hziy.

Authors:
Aditya Bardia

Clin Adv Hematol Oncol 2020 Nov;18(11):715-717

Harvard Medical School, Boston, Massachusetts.

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November 2020

The Use of Serial Circulating Tumor DNA to Detect Resistance Alterations in Progressive Metastatic Breast Cancer.

Clin Cancer Res 2021 Mar 15;27(5):1361-1370. Epub 2020 Dec 15.

Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer.

Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board-approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression.

Results: We identified 44 hormone receptor-positive, 20 HER2, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were ( < 0.0075), ( < 0.0126), ( < 0.0126), ( < 0.0455), and ( < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 ( = 0.0026, and < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA ( = 0.0042 and < 0.0001, respectively).

Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1566DOI Listing
March 2021

The adjuvant use of capecitabine for residual disease following pre-operative chemotherapy for breast cancer: Challenges applying CREATE-X to a US population.

J Oncol Pharm Pract 2020 Nov 5:1078155220971751. Epub 2020 Nov 5.

Massachusetts General Hospital, Boston, MA, USA.

Introduction: The CREATE-X study, conducted in Japan and South Korea, established capecitabine as an adjuvant treatment option for patients with triple negative breast cancer (TNBC) who have residual disease (RD) following neoadjuvant anthracycline or taxane-based chemotherapy. However, there are no reports on the tolerability and outcomes of adjuvant capecitabine in the US setting following publication of the CREATE-X data.

Methods: We retrospectively collected treatment and tolerability data from the medical records of the first 23 TNBC patients who received adjuvant capecitabine for RD post neoadjuvant chemotherapy at our institution. Disease-free survival was assessed using the Kaplan-Meier method.

Results: The median starting dosage of capecitabine was 1871 mg/m/day, most commonly divided into two daily doses on days 1-14 of each 21 day cycle. 34.8% of patients completed the treatment as prescribed. Side effects associated with treatment were common with 69.6% of patients experiencing hand-foot syndrome, 39.1% of patients experiencing diarrhea, and 13.0% of patients requiring hospitalization for side effects. Of 23 patients treated with adjuvant capecitabine, 34.8% completed the planned dose, 30.4% completed with dose reduction, and 34.8% discontinued early. At a median follow-up time of 14 months, the median disease-free survival was 22 months, with 30.4% of patients experiencing recurrence.

Conclusion: Tolerability was poor overall compared to the CREATE-X cohort. Administering adjuvant capecitabine for TNBC patients with residual disease in the United States is challenging given differences in tolerability. More research is needed to understand how poor tolerability will affect the efficacy of this approach in the US population.
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http://dx.doi.org/10.1177/1078155220971751DOI Listing
November 2020

Novel Agents for Metastatic Triple-Negative Breast Cancer: Finding the Positive in the Negative.

J Natl Compr Canc Netw 2020 10 15:1-9. Epub 2020 Oct 15.

Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Metastatic triple-negative breast cancer (TNBC) is associated with a poor prognosis, and the development of better therapeutics represents a major unmet clinical need. Although the mainstay of treatment of metastatic TNBC is chemotherapy, advances in genomics and molecular profiling have helped better define subtypes of TNBC with distinct biologic drivers to guide the therapeutic development of targeted therapies, including AKT inhibitors for PI3K/AKT-altered TNBC, checkpoint inhibitors for PD-L1-positive TNBC, and PARP inhibitors for BRCA1/2 mutant TNBC. This progress may ultimately convert TNBC from a disease traditionally defined by the absence of therapeutically actionable receptors to one that is defined by the presence of discrete molecular targets with therapeutic implications. Furthermore, antibody drug conjugates have emerged as an important therapeutic strategy to target genomically complex tumors that lack actionable oncogenes but have overexpressed actionable surface receptors such as trop-2. In this article, we discuss promising novel agents for advanced TNBC, some of which have been incorporated into current clinical practice, and others that will likely change the therapeutic landscape and redefine the TNBC terminology in the near future.
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http://dx.doi.org/10.6004/jnccn.2020.7600DOI Listing
October 2020

Clinical Outcomes of Patients with Metastatic Cancer Receiving Immune Checkpoint Inhibitors in the Inpatient Setting.

Oncologist 2021 01 8;26(1):49-55. Epub 2020 Nov 8.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: As indications for immune checkpoint inhibitor (ICI) therapy have increased in recent years, so has the proportion of patients eligible for this type of therapy. However, a lack of data exists about the risks and benefits of ICI therapy in hospitalized patients, who tend to be frailer and sicker than patients enrolled in clinical trials.

Material And Methods: We conducted a retrospective cohort study among hospitalized patients with metastatic solid tumors who received ICI therapy at a large academic cancer center over the course of 4 years. We analyzed the characteristics and outcomes of these patients and identified demographic and clinical factors that could be used to predict mortality.

Results: During the 4-year study period, 106 patients were treated with ICI therapy while admitted to the hospital; 70 (66%) had Eastern Cooperative Oncology Group Performance Status ≥2, which would have prevented them from enrolling in most clinical trials of ICIs. Fifty-two patients (49%) died either during admission or within 30 days of discharge; median overall survival was 1.0 month from discharge, and 16 patients (15%) were alive 6 months after discharge. Independent predictors of death following receipt of inpatient ICI included a diagnosis of non-small cell lung cancer relative to melanoma and prior treatment with two or more lines of therapy.

Conclusion: The poor overall outcomes observed in this study may give clinicians pause when considering ICI therapy for hospitalized patients, particularly those with characteristics that are associated with a greater risk of mortality.

Implications For Practice: Immunotherapy strategies for patients with cancer are rapidly evolving and their use is expanding, but not all patients will develop a response, and secondary toxicity can be significant and challenging. This is especially evident in hospitalized patients, where the economic cost derived from inpatient immune checkpoint inhibitor (ICI) administration is important and the clinical benefit is sometimes unclear. The poor overall outcomes evidenced in the ICI inpatient population in this study highlight the need to better identify the patients that will respond to these therapies, which will also help to decrease the financial burden imposed by these highly priced therapies.
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http://dx.doi.org/10.1002/onco.13561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794195PMC
January 2021

Phase Ib Dose-escalation/Expansion Trial of Ribociclib in Combination With Everolimus and Exemestane in Postmenopausal Women with HR, HER2 Advanced Breast Cancer.

Clin Cancer Res 2020 Dec 30;26(24):6417-6428. Epub 2020 Sep 30.

Department of Breast Medical Oncology, Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Report results of the phase Ib dose-escalation/expansion study of triplet therapy with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor (ribociclib), mTOR inhibitor (everolimus), and endocrine therapy (exemestane).

Patients And Methods: Postmenopausal women with hormone receptor-positive (HR), human epidermal growth factor receptor 2-negative (HER2), pretreated, advanced breast cancer (ABC) were enrolled. The primary objective of the dose-escalation phase was to estimate the MTD and recommended phase II dose (RP2D) of triplet therapy through evaluation of the incidence of dose-limiting toxicities. Safety, tolerability, and efficacy of the RP2D were evaluated in the dose-expansion phase in patients naïve or refractory to CDK4/6 inhibitor therapy.

Results: Patients ( = 116) received triplet therapy ( = 83 in the dose-escalation phase; = 33 in the dose-expansion phase). A dose-dependent drug-drug interaction was observed for everolimus, with exposure increasing two- to fourfold in the presence of ribociclib. The RP2D was determined to be ribociclib 300 mg once daily, 3 weeks on/1 week off in a 4-week cycle, plus everolimus 2.5 mg once daily, plus exemestane 25 mg once daily taken with food. The safety profile was consistent with the known profiles of the combination partners, and preliminary evidence of antitumor activity was observed. Higher gene expression trended with better treatment response to triplet therapy; higher gene expression of MAPK pathway genes trended with worse treatment response.

Conclusions: Triplet therapy with endocrine therapy and mTOR and CDK4/6 inhibition provides clinical benefit and an acceptable safety profile in previously treated postmenopausal women with HR, HER2 ABC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1068DOI Listing
December 2020

POLARIS: a prospective, multicenter, noninterventional study assessing palbociclib in hormone receptor-positive advanced breast cancer.

Future Oncol 2020 Nov 13;16(31):2475-2485. Epub 2020 Aug 13.

Pfizer Inc, 235 E. 42nd Street, New York, NY 10017, USA.

This report describes the rationale, purpose and design of the POLARIS study. POLARIS is an ongoing noninterventional, prospective, multicenter study. Female and male patients in the USA and Canada diagnosed with hormone receptor-positive/HER2-negative metastatic breast cancer were enrolled in the study and treated with the cyclin-dependent kinase 4/6 inhibitor palbociclib when hormone receptor-positive/HER2-negative metastatic breast cancer was deemed to be indicated by their physician. The study will provide real-world data on palbociclib prescribing and treatment patterns in routine clinical practice, associated clinical outcomes, treatment sequencing in the advanced/metastatic setting, patient quality of life and geriatric-specific assessments. The tumor genomic landscape in relation to clinical outcomes will be explored. POLARIS will identify benefits and side effects of palbociclib across multiple lines of therapy and in discrete subsets of patients. : NCT03280303 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0573DOI Listing
November 2020

Health-related quality of life in premenopausal women with hormone-receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus endocrine therapy: results from a phase III randomized clinical trial (MONALEESA-7).

Ther Adv Med Oncol 2020 26;12:1758835920943065. Epub 2020 Jul 26.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.

Background: This analysis evaluated patient-reported outcomes (PROs) to assess health-related quality of life (HRQoL) in the phase III MONALEESA-7 trial, which previously demonstrated improvements in progression-free survival (PFS) and overall survival (OS) with ribociclib (cyclin-dependent kinase 4/6 inhibitor) + endocrine therapy (ET) compared with placebo + ET in pre- and perimenopausal patients with hormone-receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC).

Methods: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire C30 (QLQ-C30) and the EQ-5D-5L were used to evaluate HRQoL.

Results: EORTC QLQ-C30 assessments were evaluable for 335 patients in the ribociclib arm and 337 patients in the placebo arm. Adherence rates at baseline and ⩾1 postbaseline time point were 90% and 83%, respectively. Patients treated with ribociclib + ET had a longer time to deterioration (TTD) ⩾ 10% in global HRQoL {hazard ratio (HR), 0.67 [95% confidence interval (CI), 0.52-0.86]}. TTD ⩾ 10% in global HRQoL was delayed in ribociclib-treated patients without with disease progression [HR, 0.31 (95% CI, 0.21-0.48)]. TTD ⩾ 10% in pain was longer with ribociclib + ET than with placebo + ET [HR, 0.65 (95% CI, 0.45-0.92)]. Patients who received a nonsteroidal aromatase inhibitor experienced similar benefits with ribociclib placebo in global HRQoL and pain.

Conclusion: HRQoL was maintained longer in patients who received ribociclib + ET placebo + ET. These data, combined with previously reported improvements in PFS and OS, support a strong clinical benefit-to-risk ratio with ribociclib-based treatment in pre- and perimenopausal patients with HR+/HER2- ABC.
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http://dx.doi.org/10.1177/1758835920943065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385843PMC
July 2020

The Art of Oncology: COVID-19 Era.

Oncologist 2020 11 10;25(11):997-1000g. Epub 2020 Sep 10.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1634/theoncologist.2020-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405267PMC
November 2020

Case 22-2020: A 62-Year-Old Woman with Early Breast Cancer during the Covid-19 Pandemic.

N Engl J Med 2020 Jul 1;383(3):262-272. Epub 2020 Jul 1.

From the Departments of Medicine (L.M.S., S.J.I., J.A.S., A.B., B.M.), Surgery (M.C.S.), Radiation Oncology (R.B.J.), Radiology (G.X.W.), and Pathology (A.L.), Massachusetts General Hospital, and the Departments of Medicine (L.M.S., S.J.I., J.A.S., A.B., B.M.), Surgery (M.C.S.), Radiation Oncology (R.B.J.), Radiology (G.X.W.), and Pathology (A.L.), Harvard Medical School - both in Boston.

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http://dx.doi.org/10.1056/NEJMcpc2002422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346678PMC
July 2020

Identification of Somatically Acquired Mutations by cfDNA Analysis in Patients with Metastatic Breast Cancer.

Clin Cancer Res 2020 Sep 22;26(18):4852-4862. Epub 2020 Jun 22.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.

Purpose: Plasma genotyping may identify mutations in potentially "actionable" cancer genes, such as , but their clinical significance is not well-defined. We evaluated the characteristics of somatically acquired mutations in patients with metastatic breast cancer (MBC).

Experimental Design: Patients with MBC undergoing routine cell-free DNA (cfDNA) next-generation sequencing (73-gene panel) before starting a new therapy were included. Somatic mutations were classified as known germline pathogenic mutations or novel variants, and linked to clinicopathologic characteristics. The effect of the PARP inhibitor, olaparib, was assessed , using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired mutation and a second patient with an acquired mutation.

Results: Among 215 patients with MBC, 29 (13.5%) had somatic cfDNA mutations [nine (4%) known germline pathogenic and rest (9%) novel variants]. Known germline pathogenic mutations were common in younger patients ( = 0.008), those with triple-negative disease ( = 0.022), and they were more likely to be protein-truncating alterations and be associated with mutations. Functional analysis of a CTC culture harboring a somatic mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic mutation showed no differential sensitivity. Across the entire cohort, APOBEC mutational signatures (COSMIC Signatures 2 and 13) and the "BRCA" mutational signature (COSMIC Signature 3) were present in mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC.

Conclusions: Somatic mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline pathogenic and novel variants.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501190PMC
September 2020

Novel antibody-drug conjugates for triple negative breast cancer.

Ther Adv Med Oncol 2020 11;12:1758835920915980. Epub 2020 May 11.

Massachusetts General Hospital Cancer Center, Harvard Medical School, 10 North Grove Street, Boston, MA 02114-2621, USA.

Triple negative breast cancer (TNBC) is a heterogenous subtype of breast cancer often associated with an aggressive phenotype and poor prognosis. Antibody-drug conjugate (ADC), comprising of a monoclonal antibody linked to a cytotoxic payload by a linker, is gaining increasing traction as an anti-cancer therapeutic. Emerging ADC drugs such as sacituzumab govitecan (IMMU-132) and trastuzumab deruxtecan (DS-8201a) are in late stages of clinical development for patients with metastatic breast cancer, including TNBC. In this article, we review and discuss the development and clinical application of ADCs in patients with advanced TNBC.
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http://dx.doi.org/10.1177/1758835920915980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222243PMC
May 2020

Optimizing Radiation Therapy to Boost Systemic Immune Responses in Breast Cancer: A Critical Review for Breast Radiation Oncologists.

Int J Radiat Oncol Biol Phys 2020 09 14;108(1):227-241. Epub 2020 May 14.

Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Immunotherapy using immune checkpoint blockade has revolutionized the treatment of many types of cancer. Radiation therapy (RT)-particularly when delivered at high doses using newer techniques-may be capable of generating systemic antitumor effects when combined with immunotherapy in breast cancer. These systemic effects might be due to the local immune-priming effects of RT resulting in the expansion and circulation of effector immune cells to distant sites. Although this concept merits further exploration, several challenges need to be overcome. One is an understanding of how the heterogeneity of breast cancers may relate to tumor immunogenicity. Another concerns the need to develop knowledge and expertise in delivery, sequencing, and timing of RT with immunotherapy. Clinical trials addressing these issues are under way. We here review and discuss the particular opportunities and issues regarding this topic, including the design of informative clinical and translational studies.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646202PMC
September 2020

Different associations of tumor PIK3CA mutations and clinical outcomes according to aspirin use among women with metastatic hormone receptor positive breast cancer.

BMC Cancer 2020 Apr 23;20(1):347. Epub 2020 Apr 23.

Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.

Introduction: The relationships among PIK3CA mutations, medication use and tumor progression remains poorly understood. Aspirin use post-diagnosis may modify components of the PI3K pathway, including AKT and mTOR, and has been associated with lower risk of breast cancer recurrence and mortality. We assessed time to metastasis (TTM) and survival with respect to aspirin use and tumor PIK3CA mutations among women with metastatic breast cancer.

Methods: Patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer treated in 2009-2016 who received tumor genotyping were included. Aspirin use between primary and metastatic diagnosis was extracted from electronic medical records. TTM and survival were estimated using Cox proportional hazards regression.

Results: Among 267 women with metastatic breast cancer, women with PIK3CA mutated tumors had longer TTM than women with PIK3CA wildtype tumors (7.1 vs. 4.7 years, p = 0.008). There was a significant interaction between PIK3CA mutations and aspirin use on TTM (p = 0.006) and survival (p = 0.026). PIK3CA mutations were associated with longer TTM among aspirin non-users (HR = 0.60 95% CI:0.44-0.82 p = 0.001) but not among aspirin users (HR = 1.57 0.86-2.84 p = 0.139). Similarly, PIK3CA mutations were associated with reduced mortality among aspirin non-users (HR = 0.70 95% CI:0.48-1.02 p = 0.066) but not among aspirin users (HR = 1.75 95% CI:0.88-3.49 p = 0.110).

Conclusions: Among women who develop metastatic breast cancer, tumor PIK3CA mutations are associated with slower time to progression and mortality only among aspirin non-users. Larger studies are needed to confirm this finding and examine the relationship among aspirin use, tumor mutation profile, and the overall risk of breast cancer progression.
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http://dx.doi.org/10.1186/s12885-020-06810-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181475PMC
April 2020

TROPiCS-02: A Phase III study investigating sacituzumab govitecan in the treatment of HR+/HER2- metastatic breast cancer.

Future Oncol 2020 Apr 30;16(12):705-715. Epub 2020 Mar 30.

Barts Cancer Institute, Queen Mary University of London, London, UK.

Patients with HR+/HER2- metastatic breast cancer (MBC) whose cancers have progressed despite conventional therapies represent an unmet clinical need. Trop-2, a transmembrane calcium signal transducer, is highly expressed in MBC and plays a role in tumor growth and progression. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate comprising an Trop-2 antibody coupled to SN-38, the active metabolite of irinotecan, via a unique hydrolyzable linker. SG has demonstrated promising activity in a Phase I/II IMMU-132-01 basket study in heavily pretreated solid tumors, including HR+/HER2- MBC. We describe the registrational Phase III TROPiCS-02 study (NCT03901339), evaluating SG versus treatment of physician's choice in HR+/HER2- MBC. Trial registration number: NCT03901339.
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http://dx.doi.org/10.2217/fon-2020-0163DOI Listing
April 2020

Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future.

Lancet 2020 03;395(10226):817-827

Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. Electronic address:

The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.
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http://dx.doi.org/10.1016/S0140-6736(20)30165-3DOI Listing
March 2020

Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis.

Clin Cancer Res 2020 06 11;26(12):2838-2848. Epub 2020 Feb 11.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Purpose: While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known.

Experimental Design: PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.

Results: Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2 (HR = 0.32; 95% PI, 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19-0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27-0.54), with no significant difference between the two groups ( = 0.60).

Conclusions: Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2 breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299787PMC
June 2020

Antibody-mediated delivery of viral epitopes to tumors harnesses CMV-specific T cells for cancer therapy.

Nat Biotechnol 2020 04 10;38(4):420-425. Epub 2020 Feb 10.

Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.

Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8 T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.
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http://dx.doi.org/10.1038/s41587-019-0404-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456461PMC
April 2020

Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion Mutations among Patients with Advanced Solid Tumors.

Clin Cancer Res 2020 06 7;26(11):2546-2555. Epub 2020 Feb 7.

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) mutations. Acquired reversions can restore function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of mutations.

Experimental Design: Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) in , and distinguishes somatic/reversion from germline mutations with high accuracy.

Results: Among 828 patients, one or more deleterious mutations were detected in 60 (7.2%) patients, including germline ( = 42) and somatic ( = 18) mutations. Common coexisting mutations included (61.6%), (30%), (26.6%), (15%), and (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.

Conclusions: cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2933DOI Listing
June 2020