Publications by authors named "Ursula A Matulonis"

155 Publications

Stepping into survivorship pilot study: Harnessing mobile health and principles of behavioral economics to increase physical activity in ovarian cancer survivors.

Gynecol Oncol 2021 Feb 23. Epub 2021 Feb 23.

Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, United States of America; Division of Gynecologic Oncology, Dana-Farber Cancer Institute, United States of America. Electronic address:

Objective: Physical activity improves physical function, quality of life, and mental health, yet fewer than 80% of ovarian cancer survivors meet activity guidelines. This pilot intervention study aimed to increase physical activity in ovarian cancer survivors by leveraging principles of behavioral economics, gamification, and social support.

Methods: This 24-week study (12-week intervention; 12-week follow-up) enrolled women with ovarian cancer after completion of first-line treatment with a self-selected "teammate." Participants used Fitbits to measure daily steps, select an increased step goal, and enroll in a collaborative game, including points and levels for achieving step goals. Primary outcomes were feasibility (defined a priori as ≥60% approach-to-consent ratio and ≥ 70% adherence to Fitbit), acceptability (≤20% of participants reporting burden or regret for participation) and preliminary efficacy (≥70% reporting increased motivation); exploratory outcomes included change in steps.

Results: We recruited 24 participants (mean age = 63 years, range = 37-79 years) with a 94% approach-to-consent ratio. All participants completed the intervention with 94% tracker adherence. At 24-week follow-up, 1/24 (≤5%) of participants reported burden; 0/24 (0%) reported regret for study participation; and 22/24 (>90%) agreed/strongly agreed that "the study motivated me to increase activity levels." Participants' mean daily steps were 6210.7 (±3328.1) at baseline and increased to 7643 (± 3610.9) steps (p < 0.001) during the 12-week intervention.

Conclusions: This pilot study demonstrated feasibility, acceptability, and preliminary efficacy, justifying a larger randomized clinical trial to test efficacy at increasing activity levels. Future studies should examine strategies for maintaining increased activity levels in survivors over time.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.023DOI Listing
February 2021

Embedding a genetic counselor into oncology clinics improves testing rates and timeliness for women with ovarian cancer.

Gynecol Oncol 2021 Feb 21;160(2):457-463. Epub 2020 Nov 21.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Population Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.

Objective: Germline genetic testing is crucial to the care of ovarian cancer patients, and as part of the guideline-based care for ovarian cancer patient's adherence to this recommendation has been low. We sought to determine whether embedding a genetic counselor (GC) within a medical and gynecologic oncology clinic would increase testing rates and improve the timeliness of testing.

Methods: Prospective cohort study of 358 ovarian cancer patients seen by medical and gynecologic oncologists between 2013 and 2015. Rates of referrals, completion of counseling, and genetic testing and timeliness of counseling were abstracted before and after a GC was embedded in the clinic in 2014. An additional year of data (2015) was collected to evaluate sustainability of the intervention.

Results: Between 2013 and 2015, 88-92% of women were referred for genetic testing, but in 2013 only 66% completed counseling and 61% were tested. After a GC was embedded in the clinic in 2014, more than 80% of referred women completed counseling and germline genetic testing. Time to genetic counseling also decreased from a median of 107 to 40 days, irrespective of age and cancer family history (p < 0.01).

Conclusions: Embedding a GC into the workflow for ovarian cancer patients is an effective way of improving access to genetic counseling, testing rates, and the timeliness of testing.
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http://dx.doi.org/10.1016/j.ygyno.2020.11.003DOI Listing
February 2021

Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer.

Cancer Res 2021 Jan 6;81(1):158-173. Epub 2020 Nov 6.

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

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes and demonstrated efficacy , validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878408PMC
January 2021

Clinical assays for assessment of homologous recombination DNA repair deficiency.

Gynecol Oncol 2020 Dec 2;159(3):887-898. Epub 2020 Oct 2.

Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America; Harvard Medical School, Boston, MA, United States of America. Electronic address:

Homologous recombination DNA repair deficiency (HRD) is a functional defect in homologous recombination DNA repair, arising from germline or somatic mutations in BRCA1/2 or other mechanisms. Cells with HRD are more sensitive to platinum and poly(ADP-ribose) polymerase inhibitors (PARPi). HRD generates permanent changes in the genome with specific, quantifiable patterns ("genomic scars"). Clinical tests for HRD, such as the Myriad genomic instability score and Foundation Medicine loss of heterozygosity test, aim to predict the presence of HRD based on genomic features. Clinical trials of PARPi in ovarian cancer have evaluated genetic mutations and HRD genomic assays as potential biomarkers of response. Patients with HRD due to BRCA1/2 mutations are more likely to respond to PARPi than those with wild-type (WT) BRCA1/2. In some clinical trials, patients with WT BRCA1/2 who were predicted to be HRD by a genomic test exhibited greater clinical benefit from PARPi than patients with WT BRCA1/2 and no evidence of HRD. HRD tests therefore hold promise as predictive biomarkers for PARPi and other DNA-damaging agents. However, HRD tests vary in terms of the specific genomic features they measure, and the methods used to determine thresholds defining patients with HRD. Also, HRD test results and PARPi responses can be discordant: for instance, tumors with reversion mutations that restore HR function still exhibit a "genomic scar" of HRD, and PARPi resistance mechanisms independent of HR can result in lack of PARPi response despite HRD. Emerging methods to predict HRD, including genomic and functional assays, may overcome some of these challenges. Evaluation of HRD in the clinical setting is an important tool that has potential to aid patient selection for PARPi and other DNA-damaging agents in ovarian cancer, but understanding the details of these tests and their limitations is critical to ensure their optimal clinical application.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.029DOI Listing
December 2020

Deciphering serous ovarian carcinoma histopathology and platinum response by convolutional neural networks.

BMC Med 2020 08 18;18(1):236. Epub 2020 Aug 18.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Background: Ovarian cancer causes 151,900 deaths per year worldwide. Treatment and prognosis are primarily determined by the histopathologic interpretation in combination with molecular diagnosis. However, the relationship between histopathology patterns and molecular alterations is not fully understood, and it is difficult to predict patients' chemotherapy response using the known clinical and histological variables.

Methods: We analyzed the whole-slide histopathology images, RNA-Seq, and proteomics data from 587 primary serous ovarian adenocarcinoma patients and developed a systematic algorithm to integrate histopathology and functional omics findings and to predict patients' response to platinum-based chemotherapy.

Results: Our convolutional neural networks identified the cancerous regions with areas under the receiver operating characteristic curve (AUCs) > 0.95 and classified tumor grade with AUCs > 0.80. Functional omics analysis revealed that expression levels of proteins participated in innate immune responses and catabolic pathways are associated with tumor grade. Quantitative histopathology analysis successfully stratified patients with different response to platinum-based chemotherapy (P = 0.003).

Conclusions: These results indicated the potential clinical utility of quantitative histopathology evaluation in tumor cell detection and chemotherapy response prediction. The developed algorithm is easily extensible to other tumor types and treatment modalities.
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http://dx.doi.org/10.1186/s12916-020-01684-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433108PMC
August 2020

Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: A phase 2 clinical trial.

Gynecol Oncol 2020 Oct 6;159(1):72-78. Epub 2020 Aug 6.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America; Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America. Electronic address:

Objective: Pegylated liposomal doxorubicin (PLD) in vitro may have immunomodulatory abilities and preclinical evidence suggests it synergizes with immune checkpoint blockade. We hypothesized that combining PLD and pembrolizumab would be active in patients with platinum-resistant ovarian cancer (PROC).

Methods: This was a single-arm, multi-center phase II trial. Eligible patients had PROC with ≤2 prior lines of cytotoxic therapy for recurrent or persistent disease. Twenty-six patients were enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks and PLD 40 mg/m IV every 4 weeks. Patients were assessed radiographically every 8 weeks. The primary endpoint was clinical benefit rate (CBR), defined as complete response (CR) + partial response (PR) + stable disease (SD) ≥24 weeks. The study was powered to detect an improvement in CBR from 25% to 50%, with rejection of the null hypothesis if at least 10 patients achieved clinical benefit. T-cell inflamed gene expression profiles (GEP) and PD-L1 were assessed and correlated with clinical outcome.

Results: Twenty-three patients were evaluable for best overall response. The study satisfied its primary endpoint, with 12 patients achieving clinical benefit for a CBR of 52.2% (95% CI 30.6-73.2%). There were 5 PRs (21.7%) and 1 CR (4.3%), for an overall response rate (ORR) of 26.1%. Six patients had SD lasting at least 24 weeks. Combination therapy was well tolerated without unexpected toxicities.

Conclusions: The combination of pembrolizumab and PLD was manageable, without unexpected toxicities, and showed preliminary evidence of clinical benefit in the treatment of platinum resistant ovarian cancer. ORR and median PFS of combination therapy in this study was higher than historical comparisons of PLD alone or anti-PD-1/PD-L1 agents alone.

Trial Registration: Clinicaltrials.gov identifier: NCT02865811.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.028DOI Listing
October 2020

Mural nodules in mucinous ovarian tumors represent a morphologic spectrum of clonal neoplasms: a morphologic, immunohistochemical, and molecular analysis of 13 cases.

Mod Pathol 2021 Mar 5;34(3):613-626. Epub 2020 Aug 5.

Division of Women's and Perinatal Pathology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Mucinous ovarian tumors rarely harbor mural nodules, which have historically been classified as sarcoma-like, anaplastic carcinomatous, or sarcomatous on the basis of predominant morphologic features. The molecular relationship between mural nodules and associated mucinous ovarian tumors remains poorly characterized, as does the molecular pathogenesis of these mural nodules. Thus, we analyzed the morphological, immunohistochemical, and genetic features of 13 mucinous ovarian tumors and associated mural nodule(s). Three harbored sarcoma-like mural nodules and ten contained anaplastic carcinomatous nodules, including 1 tumor with spatially discrete anaplastic carcinomatous and sarcomatous nodules. Twelve of 13 cases showed genetic evidence of clonality between the mural nodule(s) and associated mucinous ovarian tumor, including all three tumors with sarcoma-like morphology. Mural nodules were genetically identical in the five cases in which there were multiple discrete mural nodules that were sequenced separately. MTAP and p53 immunohistochemistry confirmed the distribution of neoplastic cells in a subset of sarcoma-like and anaplastic carcinomatous nodules. No single recurrent genetic alteration was associated with mural nodule development. No recurrent genetic differences were identified between mural nodules with sarcoma-like, anaplastic carcinomatous, and sarcomatous morphology. Of 11 patients with clinical follow-up, three died of disease 3, 8, and 9 months after diagnosis, but no recurrent genetic events were associated with poor outcome. These molecular data suggest that sarcoma-like, anaplastic carcinomatous, and sarcomatous nodules represent a morphologic spectrum of clonal neoplasms arising in mucinous ovarian tumors rather than three discrete biological entities.
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http://dx.doi.org/10.1038/s41379-020-0642-9DOI Listing
March 2021

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies.

Cancers (Basel) 2020 Jul 25;12(8). Epub 2020 Jul 25.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215-5450, USA.

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.
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http://dx.doi.org/10.3390/cancers12082054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465003PMC
July 2020

Combined CDK4/6 and PD-1 Inhibition in Refractory SMARCA4-Deficient Small-Cell Carcinoma of the Ovary, Hypercalcemic Type.

JCO Precis Oncol 2020 24;4:736-742. Epub 2020 Jun 24.

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

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http://dx.doi.org/10.1200/PO.20.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377332PMC
June 2020

Emerging drugs for the treatment of ovarian cancer: a focused review of PARP inhibitors.

Expert Opin Emerg Drugs 2020 06 22;25(2):165-188. Epub 2020 Jun 22.

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

Introduction: Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated significant anticancer activity in cancers harboring homologous recombination deficiency (HRD), exemplified by high grade serous ovarian cancer (HGSC). PARP inhibitors (PARPi) are being used in women with newly diagnosed ovarian cancer as well as in the recurrent setting. PARPi combination therapies are in development.

Areas Covered: This review discusses the treatment of ovarian cancer, key PARPi clinical trials, mechanisms of action of PARPi, and novel PARPi combination regimens under investigation. PubMed and ClinicalTrials.gov were searched for PARPi trials. Active development was confirmed via PharmaProjects.

Expert Opinion: PARPi have shown to improve progression-free survival (PFS) for women with HGSC as monotherapy in both frontline and recurrent maintenance settings and as monotherapy as treatment for recurrence. These benefits are greatest in HGSC with underlying HRD, in particular for those with deleterious mutations, and with the least benefit in cancers that are HR proficient (HRP) and BRCA wild-type (wt). Thus far, an improvement in overall survival has only been demonstrated in patients with mutated EOC treated with olaparib maintenance in the platinum sensitive recurrence setting. Novel combinations of PARPi are undergoing testing in an effort to increase PARPi efficacy in HRP or PARPi-resistant cancers.
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http://dx.doi.org/10.1080/14728214.2020.1773791DOI Listing
June 2020

Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.

Lancet Oncol 2020 07 15;21(7):957-968. Epub 2020 Jun 15.

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

Background: High-grade serous ovarian cancers show increased replication stress, rendering cells vulnerable to ATR inhibition because of near universal loss of the G1/S checkpoint (through deleterious TP53 mutations), premature S phase entry (due to CCNE1 amplification, RB1 loss, or CDKN2A mRNA downregulation), alterations of homologous recombination repair genes, and expression of oncogenic drivers (through MYC amplification and other mechanisms). We hypothesised that the combination of the selective ATR inhibitor, berzosertib, and gemcitabine could show acceptable toxicity and superior efficacy to gemcitabine alone in high-grade serous ovarian cancer.

Methods: In this multicentre, open-label, randomised, phase 2 study, 11 different centres in the US Experimental Therapeutics Clinical Trials Network enrolled women (aged ≥18 years) with recurrent, platinum-resistant high-grade serous ovarian cancer (determined histologically) and Eastern Cooperative Oncology Group performance status of 0 or 1, who had unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting. Eligible patients were randomly assigned (1:1) to receive intravenous gemcitabine (1000 mg/m) on day 1 and day 8, or gemcitabine plus intravenous berzosertib (210 mg/m) on day 2 and day 9 of a 21-day cycle until disease progression or intolerable toxicity. Randomisation was done centrally using the Theradex Interactive Web Response System, stratified by platinum-free interval, and with a permuted block size of six. Following central randomisation, patients and investigators were not masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival, and analyses included all patients who received at least one dose of the study drugs. The study is registered with ClinicalTrials.gov, NCT02595892, and is active but closed to enrolment.

Findings: Between Feb 14, 2017, and Sept 7, 2018, 88 patients were assessed for eligibility, of whom 70 were randomly assigned to treatment with gemcitabine alone (36 patients) or gemcitabine plus berzosertib (34 patients). At the data cutoff date (Feb 21, 2020), the median follow-up was 53·2 weeks (25·6-81·8) in the gemcitabine plus berzosertib group and 43·0 weeks (IQR 23·2-69·1) in the gemcitabine alone group. Median progression-free survival was 22·9 weeks (17·9-72·0) for gemcitabine plus berzosertib and 14·7 weeks (90% CI 9·7-36·7) for gemcitabine alone (hazard ratio 0·57, 90% CI 0·33-0·98; one-sided log-rank test p=0·044). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (14 [39%] of 36 patients in the gemcitabine alone group vs 16 [47%] of 34 patients in the gemcitabine plus berzosertib group) and decreased platelet count (two [6%] vs eight [24%]). Serious adverse events were observed in ten (28%) patients in the gemcitabine alone group and nine (26%) patients in the gemcitabine plus berzosertib group. There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the gemcitabine plus berzosertib group due to pneumonitis.

Interpretation: To our knowledge, this is the first randomised study of an ATR inhibitor in any tumour type. This study shows a benefit of adding berzosertib to gemcitabine in platinum-resistant high-grade serous ovarian cancer. This combination warrants further investigation in this setting.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30180-7DOI Listing
July 2020

A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.

Nat Med 2020 05 11;26(5):792-802. Epub 2020 May 11.

Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption. Here, we have developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We analyzed 216,490 cells and nuclei from 40 samples across 23 specimens spanning eight tumor types of varying tissue and sample characteristics. We evaluated protocols by cell and nucleus quality, recovery rate and cellular composition. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types, but at different proportions. Our work provides guidance for studies in a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.
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http://dx.doi.org/10.1038/s41591-020-0844-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220853PMC
May 2020

COVID-19 and ovarian cancer: Exploring alternatives to intravenous (IV) therapies.

Gynecol Oncol 2020 07 29;158(1):34-36. Epub 2020 Apr 29.

The Ohio State University, James Cancer Center, Columbus, OH, USA.

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http://dx.doi.org/10.1016/j.ygyno.2020.04.703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188656PMC
July 2020

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.

Nat Commun 2020 03 19;11(1):1459. Epub 2020 Mar 19.

Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
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http://dx.doi.org/10.1038/s41467-020-15315-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081234PMC
March 2020

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers.

BMC Cancer 2020 Mar 12;20(1):197. Epub 2020 Mar 12.

Department of Computer Science and Engineering, University of Connecticut, Institute of System Genomics, Boston, MA, USA.

Background: BRCA1/2 germline mutation related cancers are candidates for new immune therapeutic interventions. This study was a hypothesis generating exploration of genomic data collected at diagnosis for 19 patients. The prominent tumor mutation burden (TMB) in hereditary breast and ovarian cancers in this cohort was not correlated with high global immune activity in their microenvironments. More information is needed about the relationship between genomic instability, phenotypes and immune microenvironments of these hereditary tumors in order to find appropriate markers of immune activity and the most effective anticancer immune strategies.

Methods: Mining and statistical analyses of the original DNA and RNA sequencing data and The Cancer Genome Atlas data were performed. To interpret the data, we have used published literature and web available resources such as Gene Ontology, The Cancer immunome Atlas and the Cancer Research Institute iAtlas.

Results: We found that BRCA1/2 germline related breast and ovarian cancers do not represent a unique phenotypic identity, but they express a range of phenotypes similar to sporadic cancers. All breast and ovarian BRCA1/2 related tumors are characterized by high homologous recombination deficiency (HRD) and low aneuploidy. Interestingly, all sporadic high grade serous ovarian cancers (HGSOC) and most of the subtypes of triple negative breast cancers (TNBC) also express a high degree of HRD.

Conclusions: TMB is not associated with the magnitude of the immune response in hereditary BRCA1/2 related breast and ovarian cancers or in sporadic TNBC and sporadic HGSOC. Hereditary tumors express phenotypes as heterogenous as sporadic tumors with various degree of "BRCAness" and various characteristics of the immune microenvironments. The subtyping criteria developed for sporadic tumors can be applied for the classification of hereditary tumors and possibly also characterization of their immune microenvironment. A high HRD score may be a good candidate biomarker for response to platinum, and potentially PARP-inhibition.

Trial Registration: Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent TNBC or HGSOC (NCT01623349), first posted on June 20, 2012. The design and the outcome of the clinical trial is not in the scope of this study.
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http://dx.doi.org/10.1186/s12885-020-6605-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068944PMC
March 2020

Results of an abbreviated phase II study of AKT inhibitor MK-2206 in the treatment of recurrent platinum-resistant high grade serous ovarian, fallopian tube, or primary peritoneal carcinoma (NCT 01283035).

Gynecol Oncol Rep 2020 May 3;32:100546. Epub 2020 Feb 3.

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

Platinum-resistant, recurrent, high grade epithelial ovarian carcinoma remains challenging to treat. Chemotherapy produces limited responses with modest survival benefits in the treatment of recurrent disease. In this context, targeted therapies may improve upon conventional therapies. PI3K/AKT pathway alterations are frequently found in several cancer types, including ovarian cancer, and thus AKT inhibition is a rational targeted therapy. Here we report the results of an abbreviated trial of AKT inhibitor MK-2206 in platinum resistant high grade serous ovarian, fallopian tube, and primary peritoneal cancer with PTEN loss.
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http://dx.doi.org/10.1016/j.gore.2020.100546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021536PMC
May 2020

Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer.

Gynecol Oncol 2020 05 18;157(2):379-385. Epub 2020 Feb 18.

Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; Sarah Cannon Research Institute, Nashville, TN, United States. Electronic address:

Purpose: To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FRα) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FRα-positive, platinum-resistant ovarian cancer.

Methods: Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg, adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FRα positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined.

Results: Sixty-six patients, with a median of 3 prior lines of therapy (range, 1-8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (≤grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxicities. Six cases of pneumonitis (9%; all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naïve, less heavily pretreated (1-2 prior lines), and whose tumors exhibited medium/high FRα expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months).

Conclusion: The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant, recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.037DOI Listing
May 2020

A Randomized Phase II Trial of Epigenetic Priming with Guadecitabine and Carboplatin in Platinum-resistant, Recurrent Ovarian Cancer.

Clin Cancer Res 2020 03 12;26(5):1009-1016. Epub 2019 Dec 12.

Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Platinum resistance in ovarian cancer is associated with epigenetic modifications. Hypomethylating agents (HMA) have been studied as carboplatin resensitizing agents in ovarian cancer. This randomized phase II trial compared guadecitabine, a second-generation HMA, and carboplatin (G+C) against second-line chemotherapy in women with measurable or detectable platinum-resistant ovarian cancer.

Patients And Methods: Patients received either G+C (guadecitabine 30 mg/m s.c. once-daily for 5 days and carboplatin) or treatment of choice (TC; topotecan, pegylated liposomal doxorubicin, paclitaxel, or gemcitabine) in 28-day cycles until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were RECIST v1.1 and CA-125 response rate, 6-month PFS, and overall survival (OS).

Results: Of 100 patients treated, 51 received G+C and 49 received TC, of which 27 crossed over to G+C. The study did not meet its primary endpoint as the median PFS was not statistically different between arms (16.3 weeks vs. 9.1 weeks in the G+C and TC groups, respectively; = 0.07). However, the 6-month PFS rate was significantly higher in the G+C group (37% vs. 11% in TC group; = 0.003). The incidence of grade 3 or higher toxicity was similar in G+C and TC groups (51% and 49%, respectively), with neutropenia and leukopenia being more frequent in the G+C group.

Conclusions: Although this trial did not show superiority for PFS of G+C versus TC, the 6-month PFS increased in G+C treated patients. Further refinement of this strategy should focus on identification of predictive markers for patient selection.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056559PMC
March 2020

Transcriptome analysis reveals overlap in fusion genes in a phase I clinical cohort of TNBC and HGSOC patients treated with buparlisib and olaparib.

J Cancer Res Clin Oncol 2020 Feb 19;146(2):503-514. Epub 2019 Nov 19.

Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Purpose: Fusion genes can be therapeutically relevant if they result in constitutive activation of oncogenes or repression of tumor suppressors. However, the prevalence and role of fusion genes in female cancers remain largely unexplored. Here, we investigate the fusion gene landscape in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), two subtypes of female cancers with high molecular similarity but limited treatment options at present.

Methods: RNA-seq was utilized to identify fusion genes in a cohort of 18 TNBC and HGSOC patients treated with the PI3K inhibitor buparlisib and the PARP inhibitor olaparib in a phase I clinical trial (NCT01623349). Differential gene expression analysis was performed to assess the function of fusion genes in silico. Finally, these findings were correlated with the reported clinical outcomes.

Results: A total of 156 fusion genes was detected, whereof 44/156 (28%) events occurred in more than one patient. Low recurrence across samples indicated that the majority of fusion genes were private passenger events. The long non-coding RNA MALAT1 was involved in 97/156 (62%) fusion genes, followed in prevalence by MUC16, FOXP1, WWOX and XIST. Gene expression of FOXP1 was significantly elevated in patients with vs. without FOXP1 fusion (P= 0.02). From a clinical perspective, FOXP1 fusions were associated with a favorable overall survival.

Conclusions: In summary, this study provides the first characterization of fusion genes in a cohort of TNBC and HGSOC patients. An improved mechanistic understanding of fusion genes will support the future identification of innovative therapeutic approaches for these challenging diseases.
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http://dx.doi.org/10.1007/s00432-019-03078-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985087PMC
February 2020

Phase II, 2-stage, 2-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer.

Int J Cancer 2020 07 13;147(2):413-422. Epub 2019 Dec 13.

Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M. D. Anderson Cancer Center, Houston, TX.

Endometrial cancers have high rates of phosphoinositide 3-kinase (PI3K) pathway alterations. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized patients with tumors harboring PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. A Phase II study was performed in patients with recurrent endometrial cancer; all histologies except carcinosarcoma were eligible. Up to two prior chemotherapy lines were permitted, excluding prior treatment with PI3K pathway inhibitors. The first 18 patients were treated with MK-2206 200 mg weekly. Due to unacceptable toxicity, dose was reduced to 135 mg. Co-primary endpoints were objective response rate (ORR) and progression-free survival at 6 months (6moPFS). Thirty-seven patients were enrolled (one ineligible). By somatic PIK3CA mutation analysis, nine patients were mutant (MT) [one with partial response (PR)/6moPFS, two with 6moPFS]. Twenty-seven patients were wild-type (WT) (one PR and four 6moPFS). Most common toxicities were rash (44%), fatigue (41%), nausea (42%) and hyperglycemia (31%). Grade 3 and 4 toxicities occurred in 25 and 17% of patients, respectively. Exploratory analysis found serous histology had greater 6moPFS as compared to all other histologies (5/8 vs. 2/28, p = 0.003). PTEN expression was associated with median time to progression (p = 0.04). No other significant associations with PI3K pathway alterations were identified. There is limited single agent activity of MK-2206 in PIK3CA MT and PIK3CA WT endometrial cancer populations. Activity was detected in patients with serous histology and due to their poor outcomes warrants further study (NCT01307631).
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http://dx.doi.org/10.1002/ijc.32783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214201PMC
July 2020

Prediagnosis and postdiagnosis smoking and survival following diagnosis with ovarian cancer.

Int J Cancer 2020 Aug 2;147(3):736-746. Epub 2019 Dec 2.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Little is known about the influence of prediagnosis and postdiagnosis smoking and smoking cessation on ovarian cancer survival. We investigated this relationship in two prospective cohort studies, the Nurses' Health Study (NHS) and NHSII. Analyses included 1,279 women with confirmed invasive, Stage I-III epithelial ovarian cancer. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for ovarian cancer-specific mortality by smoking status, adjusting for age and year of diagnosis, tumor stage, histologic subtype, body mass index and nonsteroidal anti-inflammatory use (postdiagnosis models only). When examining prediagnosis smoking status (assessed a median of 12 months before diagnosis), risk of death was significantly increased for former smokers (HR = 1.19, 95% CI: 1.02-1.39), and suggestively for current smokers (HR = 1.21, 95% CI: 0.96-1.51) vs. never smokers. Longer smoking duration (≥20 years vs. never, HR = 1.23, 95% CI: 1.05-1.45) and higher pack-years (≥20 pack-years vs. never, HR = 1.28, 95% CI: 1.07-1.52) were also associated with worse outcome. With respect to postdiagnosis exposure, women who smoked ≥15 cigarettes per day after diagnosis (assessed a median of 11 months after diagnosis) had increased mortality compared to never smokers (HR = 2.34, 95% CI: 1.63-3.37). Those who continued smoking after diagnosis had 40% higher mortality (HR = 1.40, 95% CI: 1.05-1.87) compared to never smokers. Overall, our results suggest both prediagnosis and postdiagnosis smoking are associated with worse ovarian cancer outcomes.
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http://dx.doi.org/10.1002/ijc.32773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758910PMC
August 2020

Choosing wisely: Selecting PARP inhibitor combinations to promote anti-tumor immune responses beyond BRCA mutations.

Gynecol Oncol 2020 02 17;156(2):488-497. Epub 2019 Oct 17.

Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

PARP inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP inhibitor combinations.
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http://dx.doi.org/10.1016/j.ygyno.2019.09.021DOI Listing
February 2020

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 10. Epub 2019 Oct 10.

Department of Medical Oncology, Massachusetts General Hospital, Boston.

Importance: To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease.

Objective: To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer.

Design, Setting, And Participants: A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy.

Interventions: Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks.

Main Outcome And Measures: The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy.

Results: Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater.

Conclusions And Relevance: The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.
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http://dx.doi.org/10.1001/jamaoncol.2019.3343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802049PMC
October 2019

Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial.

J Clin Oncol 2019 12 16;37(34):3183-3191. Epub 2019 Sep 16.

Nordic Society of Gynaecological Oncology and Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer.

Patients And Methods: Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline mutation-gmut and non-gmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post-random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs.

Results: In the gmut and non-gmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the gmut and non-gmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons.

Conclusion: Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.
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http://dx.doi.org/10.1200/JCO.19.00917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881097PMC
December 2019

Results of an abbreviated Phase Ib study of the HDAC6 inhibitor ricolinostat and paclitaxel in recurrent ovarian, fallopian tube, or primary peritoneal cancer.

Gynecol Oncol Rep 2019 Aug 10;29:118-122. Epub 2019 Aug 10.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States of America.

Peripheral neuropathy is a common side effect of chemotherapeutic agents that frequently necessitates dose-reduction, truncation of, or change in therapy. HDAC6 inhibition has demonstrated preclinical efficacy in preventing and/or reversing chemotherapy-induced peripheral neuropathy and furthermore has demonstrated synergistic antitumor activity with various chemotherapies. Here, we report the abbreviated results of a Phase Ib trial of ricolinostat, an HDAC6-specific inhibitor, in combination with paclitaxel, in the treatment of recurrent ovarian, fallopian tube, or primary peritoneal cancer.
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http://dx.doi.org/10.1016/j.gore.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712364PMC
August 2019

Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer.

Mol Cancer Res 2019 11 28;17(11):2281-2293. Epub 2019 Aug 28.

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

High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including (BCL-XL) and (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. IMPLICATIONS: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-1243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825578PMC
November 2019

Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.

J Clin Oncol 2019 10 28;37(30):2786-2794. Epub 2019 Aug 28.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).

Methods: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/ (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of ; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.

Results: Thirty-three patients were enrolled. No patient with -mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not -mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.

Conclusion: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-mutated ECs was low.
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http://dx.doi.org/10.1200/JCO.19.01021DOI Listing
October 2019