Publications by authors named "Pedro Exman"

14 Publications

  • Page 1 of 1

HER2-positive metastatic breast cancer: a comprehensive review.

Clin Adv Hematol Oncol 2021 Jan;19(1):40-50

Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Cases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent approximately 15% to 20% of all breast cancers. Historically, this subtype of breast cancer was associated with an increased risk for the development of systemic and brain metastases and poor overall survival. The introduction of trastuzumab dramatically changed the outcomes of patients with HER2-positive disease, with many demonstrating outcomes similar to those of patients with luminal tumors. Currently, the first-line standard of care for patients with HER2-positive metastatic breast cancer is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. After progression, the standard of care is trastuzumab emtansine (T-DM1). Although the treatment choices for patients whose disease has progressed on these agents are more limited, promising new drugs have emerged as effective options, including tucatinib and trastuzumab deruxtecan, which were recently approved by the US Food and Drug Administration. Finding the best treatment sequencing for each patient, developing reliable predictive biomarkers, and understanding the mechanisms of resistance to these drugs are necessary to maximize patient outcomes and quality of life. In this review, we analyze the management strategies for metastatic HER2-positive breast cancer, address specific situations, such as the treatment of patients with brain metastases, and discuss future directions in the treatment of this subtype.
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January 2021

Birthweight and Chemotherapy Exposure in Women Diagnosed with Breast Cancer during Pregnancy.

Am J Perinatol 2020 Sep 24. Epub 2020 Sep 24.

Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts.

Objective:  Breast cancer is one of the most frequently diagnosed cancers in pregnancy and is commonly treated with chemotherapy. To date, studies examining effects of chemotherapy during pregnancy on fetal growth have yielded conflicting results, and most are limited by small sample sizes or are nonspecific with respect to cytotoxic regimen or type of cancer treated. We sought to evaluate the effect of chemotherapy for breast cancer in pregnancy on birthweight and small for gestational age infants.

Study Design:  This is a retrospective cohort study of 74 women diagnosed with pathologically confirmed breast cancer during pregnancy between 1997 and 2018 at one of three academic medical centers, who had a singleton birth with known birthweight. Forty-nine received chemotherapy and 25 did not receive chemotherapy. Linear regression modeling was used to compare birthweight (by gestational age and sex-specific -score) by chemotherapy exposure. Subanalyses of specific chemotherapy regimen and duration of chemotherapy exposure were also performed. Placental, neonatal, and maternal outcomes were also analyzed by chemotherapy exposure.

Results:  In the adjusted model, chemotherapy exposure was associated with lower birthweight (∆ -score =  - 0.49,  = 0.03), but similar rates of small for gestational age (defined as birthweight <10th percentile for gestational age) infants (8.2 vs. 8.0%,  = 1.0; Fisher's exact test). Each additional week of chemotherapy (∆ -score =  - 0.05,  = 0.03) was associated with decreased birthweight, although no association was found with specific chemotherapy regimen. Chemotherapy exposure was associated with lower median placental weight percentile by gestational age (9th vs. 75th,  < 0.05). Secondary maternal outcomes were similar between the group that did and did not receive chemotherapy.

Conclusion:  Chemotherapy for breast cancer in pregnancy in this cohort is associated with lower birthweight but no difference in the rate of small for gestational age infants.

Key Points: · Chemotherapy for breast cancer in pregnancy is associated with decreased birthweight but similar rates of small for gestational age infants.. · Birthweight did not differ according to chemotherapy regimen.. · There is no difference in the rate of small for gestational age infants..
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http://dx.doi.org/10.1055/s-0040-1717075DOI Listing
September 2020

Identifying Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.

JCO Precis Oncol 2019 15;3. Epub 2019 Nov 15.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling.

Patients And Methods: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of mutations, and survival. Associations were calculated using Fisher's exact test.

Results: We identified a total of 1,045 patients with metastatic breast cancer without amplification who had available genomic testing results. Of these, 42 patients were found to have mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing.

Conclusion: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.
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http://dx.doi.org/10.1200/PO.19.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446367PMC
November 2019

Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER Metastatic Breast Cancer.

Clin Cancer Res 2020 Nov 28;26(22):5974-5989. Epub 2020 Jul 28.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER breast cancer.

Experimental Design: We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing in paired pretreatment and postresistance biopsies from 60 patients with ER metastatic breast cancer who had developed resistance to ER-targeted therapy. Furthermore, we performed experiments to validate resistance genes/pathways and to identify drug combinations to overcome resistance.

Results: Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. The FGFR pathway was altered via , or amplifications or mutations in 24 (40%) of the postresistance biopsies. In 12 of the 24 postresistance tumors exhibiting FGFR/FGF alterations, these alterations were acquired or enriched under the selective pressure of ER-directed therapy. experiments in ER breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant cell lines demonstrated that FGFR/FGF induced resistance through ER reprogramming and activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a SHP2 inhibitor.

Conclusions: Our results suggest that FGFR pathway is a distinct mechanism of acquired resistance to ER-directed therapy that can be overcome by FGFR and/or MAPK pathway inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3958DOI Listing
November 2020

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Clin Cancer Res 2020 06 13;26(11):2556-2564. Epub 2020 Mar 13.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.

Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).

Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654718PMC
June 2020

Tumor Mutational Burden and Alterations as Molecular Correlates of Response to PD-1/L1 Blockade in Metastatic Triple-Negative Breast Cancer.

Clin Cancer Res 2020 06 4;26(11):2565-2572. Epub 2020 Feb 4.

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

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.

Experimental Design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.

Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; = 0.04), while alterations (29%) were associated with significantly lower ORR (6% vs. 48%; = 0.01), shorter PFS (2.3 vs. 6.1 months; = 0.01), and shorter OS (9.7 vs. 20.5 months; = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy ( = 90) and non-ICI regimens ( = 169).

Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269810PMC
June 2020

Response to Olaparib in a Patient with Germline Mutation and Breast Cancer Leptomeningeal Carcinomatosis.

NPJ Breast Cancer 2019 29;5:46. Epub 2019 Nov 29.

1Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA.

Leptomeningeal carcinomatosis (LC) is a devastating complication of metastatic cancer that disproportionately affects patients with advanced breast cancer. Moreover, those with BRCA1/2-mutated disease more often experience leptomeningeal metastasis. Treatment options for LC are limited and often include significant toxicities. PARP inhibitors offer an important potential treatment for patients with BRCA1/2-mutated breast and ovarian cancers, but clinical studies excluded patients with central nervous system (CNS) metastases, including LC. Efficacy data in this area are therefore limited, although a phase I study of olaparib in glioblastoma did show CNS penetration. Here we report a case of a patient with BRCA2-mutated breast cancer and solitary recurrence in the leptomeninges with ongoing complete response to treatment with the PARP inhibitor olaparib. PARP inhibitors may be an important treatment option for patients with BRCA-mutated disease and LC, and warrant further study.
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http://dx.doi.org/10.1038/s41523-019-0139-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884546PMC
November 2019

Evidence to date: talazoparib in the treatment of breast cancer.

Onco Targets Ther 2019 2;12:5177-5187. Epub 2019 Jul 2.

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

Approximately 5-10% of all patients diagnosed with breast cancer have germline mutations, which make their disease more susceptible to DNA-damaging agents and a new class of drugs known as poly(ADP-ribose) polymerase (PARP) inhibitors. Talazoparib is a new PARP inhibitor that has been recently approved for use in patients with metastatic breast cancer with germline mutations after a phase III trial showed superior progression-free survival when compared to standard chemotherapy. In this review, we analyze the development of talazoparib as well as its safety profile and the potential role of the combination therapy with standard cytotoxic drugs and with novel therapies.
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http://dx.doi.org/10.2147/OTT.S184971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612288PMC
July 2019

How we treat locally advanced HER2-positive breast cancer.

Clin Adv Hematol Oncol 2019 May;17(5):271-280

Dana-Farber Cancer Institute, Boston, Massachusetts.

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May 2019

Cancer During Pregnancy: The Oncologist Overview.

World J Oncol 2019 Feb 26;10(1):28-34. Epub 2019 Feb 26.

Division of Hematology and Oncology, University of Tennessee Health Science Center/West Cancer Center, Memphis, TN, USA.

Although a rare and challenging condition, cancer during pregnancy should promptly be identified and treated. Not only standards of care guidelines for the underlying disease are taken into account, but also fetal safety might be weighted for clinical decisions. Frequent lack of experience and knowledge about this condition could lead to late diagnosis, imprecise management, suboptimal treatment and fetal and maternal harm. Therefore, this review aims to summarize the current evidence regarding the epidemiology, clinical presentation, diagnostic workup, staging and treatment, including novel treatment modalities for patients diagnosed with cancer during pregnancy.
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http://dx.doi.org/10.14740/wjon1177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396773PMC
February 2019

How Old is Too Old? Breast Cancer Treatment in Octogenarians.

Ann Surg Oncol 2018 06 9;25(6):1458-1460. Epub 2018 Apr 9.

Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1245/s10434-018-6457-yDOI Listing
June 2018

De-escalating treatment in the adjuvant setting in HER2-positive breast cancer.

Future Oncol 2018 Apr 28;14(10):937-945. Epub 2018 Mar 28.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

The decision to offer adjuvant therapy to patients with early-stage cancer relies on factors related to the risk of disease recurrence, degree of benefit with the proposed therapy and the associated risk of toxicities. For patients with stages II and III HER2-positive breast cancer, administering 1 year of trastuzumab plus comprehensive chemotherapy is the standard of care. However, the pivotal adjuvant trials had very few older patients and patients with small HER2-positive tumors. In this review, we will discuss the clinical data regarding strategies to de-escalate adjuvant systemic therapy in patients with early stage HER2-positive disease.
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http://dx.doi.org/10.2217/fon-2017-2500DOI Listing
April 2018

Breast cancer-specific survival by age: Worse outcomes for the oldest patients.

Cancer 2018 05 2;124(10):2184-2191. Epub 2018 Mar 2.

Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Although breast cancer often is perceived to be indolent in older women, breast cancer outcomes in the oldest patients are variable. In the current study, the authors examined breast cancer-specific death by age, stage, and disease subtype in a large, population-based cohort.

Methods: Using Surveillance, Epidemiology, and End Results data, a total of 486,118 women diagnosed with American Joint Committee on Cancer stage I to IV breast cancer between 2000 and 2012 were identified. Using a series of Fine and Gray regression models to account for competing risk, the authors examined the risk of breast cancer-specific death by age and stage (I-IV) for subcohorts with hormone receptor (HR)-positive, HR-negative, human epidermal growth factor receptor 2-positive, and triple-negative disease, adjusting for demographic and clinical variables.

Results: Overall, 18% of women were aged 65 to 74 years, 13% were aged 75 to 84 years, and 4% were aged ≥85 years. Regardless of stage of disease within the HR-positive and HR-negative cohorts, patients aged ≥75 years (vs those aged 55-64 years) experienced a higher adjusted hazard of breast cancer-specific death, which was particularly evident for those with early-stage, HR-positive disease (hazard ratio for those aged 75-84 years, 1.88 [95% confidence interval, 1.68-2.09] and hazard ratio for those aged ≥85 years, 3.59 [95% confidence interval, 3.12-4.13] [both for stage I disease]). In the cohorts with human epidermal growth factor receptor 2-positive and triple-negative disease, women aged ≥70 years had a consistently higher risk of breast cancer-specific death across disease stages (vs those aged 51-60 years), with the exception of stage IV triple-negative disease.

Conclusions: Older patients experience worse breast cancer outcomes, regardless of disease subtype and stage. With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority. Cancer 2018;124:2184-91. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935594PMC
May 2018

Primary ovary choriocarcinoma: individual DNA polymorphic analysis as a strategy to confirm diagnosis and treatment.

Rare Tumors 2013 Apr 13;5(2):89-92. Epub 2013 Jun 13.

Department of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo.

Primary choriocarcinoma of the ovary is rare. Furthermore, this tumor can arise from gestational tissue or pure germ cells of the ovary, with the latter resulting in non-gestational choriocarcinoma. While the clinical characteristics and histology of both tumor types are identical, differentiation of these tumors is necessary for effective treatment. One strategy for the differentiation of these tumors types is to assay for the presence of paternal DNA. Accordingly, in the present case, a patient with primary choriocarcinoma of the ovary with a non-gestational origin was confirmed by DNA analysis. The patient subsequently exhibited an excellent response to chemotherapy, and following surgery, achieved complete remission. A pathological analysis of surgical specimens further confirmed the absence of tumor.
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http://dx.doi.org/10.4081/rt.2013.e24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719119PMC
April 2013