Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline ...(g)
/
mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)
/
mutations or g/s mutations in homologous recombination (HR)-related genes other than
2.
Eligible patients had MBC with measurable disease and germline mutations in non-
/
HR-related genes (cohort 1) or somatic mutations in these genes or
/
(cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).
Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in
s
/
,
or
. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with g
(ORR, 82%) and s
/
(ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable NA) for g
and 6.3 months (90% CI, 4.4 months to NA) for s
/
mutation carriers. No responses were observed with
or
mutations alone.
PARP inhibition is an effective treatment for patients with MBC and g
or s
/
mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond g
/
mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.
Germline genetic evaluation is indicated for all patients with epithelial ovarian cancer (EOC). For testing to have clinical utility, results must be documented within the electronic medical record ...(EMR) and accessible to providers at the point of care, which can be challenging in the context of current EMR limitations and genetic testing processes. We examined the receipt of genetics services and EMR capture of genetic testing results in patients with EOC. We conducted a retrospective chart review to examine germline genetic evaluations among patients with EOC seen by a gynecologic or medical oncologist at the University of Pennsylvania in 2016. EMRs were reviewed to determine: (1) if patients were referred for genetic evaluation; (2) if genetic testing was performed; (3) if results were documented in office notes, scanned third‐party test reports, and/or the EMR problem list; (4) if provider notes correctly listed the variant classification. Overall, 413 (62%) of patients had documented genetic testing. Genetic testing was documented in almost all provider notes (96%) and the majority of scanned EMR reports (64%). Pathogenic variants were found in 119 (29%) individuals; the majority (70%) had genetic testing documented within EMR problem lists. Provider notes were highly accurate in describing variant classification. In this study, genetic testing was performed and documented in the EMR for most EOC patients. Approximately one‐third of those tested did not have scanned test reports specifying variant found, limiting the utility of test results for cascade testing and therapeutic decisions.
Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and ...Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort.
A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1–7 and olaparib 300 mg orally twice daily, days 1–28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients.
Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5–8.2) and 8.2 months (3.6 months–not determined) for patients with BRCA1 mutations.
Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.
•Combination olaparib and ceralasertib is tolerable at the current RP2D.•No RECIST radiological responses occurred and PFS was 4.2 months.•PFS was 8.2 months in 3 subjects with BRCA1 mutations.•CA-125 responses by GCIG criteria were seen in 3 of 11 evaluable subjects.•A signal of activity was seen in DNA repair deficient platinum resistant HGSOC.
Next-generation or massively parallel sequencing has transformed the landscape of genetic testing for cancer susceptibility. Panel-based genetic tests evaluate multiple genes simultaneously and ...rapidly. Because these tests are frequently offered in clinical settings, understanding their clinical validity and utility is critical. When evaluating the inherited risk of breast and ovarian cancers, panel-based tests provide incremental benefit compared with
BRCA1
2
genetic testing. For inherited risk of other cancers, such as colon cancer and pheochromocytoma-paraganglioma, the clinical utility and yield of panel-based testing are higher; in fact, simultaneous evaluation of multiple genes has been the historical standard for these diseases. Evaluating inherited risk with panel-based testing has recently entered clinical practice for prostate and pancreatic cancers, with potential therapeutic implications. The resulting variants of uncertain significance and mutations with unclear actionability pose challenges to service providers and patients, underscoring the importance of genetic counseling and data-sharing initiatives. This review explores the evolving merits, challenges, and nuances of panel-based testing for cancer susceptibility.
The landscape of genetic testing for breast cancer susceptibility has transformed dramatically over the last decade and a half. Traditionally, the process of genetic testing resided fully within a ...medical infrastructure, from identification of appropriate testing candidates to gene selection to risk mitigation recommendations. More recently, decreasing costs, advancing technology, and a growing understanding of therapeutic implications of certain genetic test results have led to more widespread uptake of testing that increasingly involves broad multigene panels. Germline genetic testing for breast cancer susceptibility can now be obtained through one of three approaches: through clinical care; a direct‐to‐consumer (DTC) approach that is entirely consumer‐driven; or a hybrid, patient‐initiated, provider‐mediated model. Increased access to testing has led to extensive dialogue about the best way to conduct testing and act on results. Points of discussion include: selection of appropriate candidates for genetic testing; optimal composition of genes on panels; informed consent; safe return of results; privacy; and legal protections for those found to have relevant pathogenic or likely pathogenic variants. As more individuals undergo genetic testing, a growing population of individuals with inherited breast cancer predisposition informs optimal management of cancer risk and also highlights unanswered questions. This article aims to review the current state of genetic testing for inherited breast cancer susceptibility including testing approaches, the legal, ethical and social landscape, and selected contemporary management issues.
Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for
mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover ...mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function
mutations in 25% of patients with resistance.
activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight
loss as a recurrent mechanism of resistance to PI3Kα inhibition.
Abstract
Background
The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene ...germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies.
Methods
Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer.
Results
Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval CI = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer.
Conclusions
The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.
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