Impact of homologous recombination status and responses with veliparib combined with first-line chemotherapy in ovarian cancer in the Phase 3 VELIA/GOG-3005 study.

OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy. METHODS: Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks. RESULTS: Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53-1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56-1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control. CONCLUSIONS: These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.

Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVES: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status. METHODS: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status. RESULTS: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates). CONCLUSIONS: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone.

Impact of veliparib, paclitaxel dosing regimen, and germline BRCA status on the primary treatment of serous ovarian cancer - an ancillary data analysis of the VELIA trial.

OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status. METHODS: Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status. RESULTS: 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCAwt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n = 211) and gBRCAwt (n = 902) subgroups. CONCLUSIONS: DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.

Non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes.

Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

Tissue-Specific Carcinogens as Soil to Seed BRCA1/2-Mutant Hereditary Cancers.

Despite their ubiquitous expression, the inheritance of monoallelic germline mutations in breast cancer susceptibility gene type 1 or 2 (BRCA1/2) poses tissue-specific variations in cancer risks and primarily associate with familial breast and ovarian cancers. The molecular basis of this tissue-specific tumor incidence remains unknown and intriguing to cancer researchers. A plethora of recent reports support the idea that several nongenetic factors present in the tissue microenvironment could induce tumors in the mutant BRCA1/2 background. This Opinion article summarizes the recent advances on tissue-specific carcinogens and their complex crosstalk with the compromised DNA repair machinery of BRCA1/2-mutant cells. Finally, we present our perspective on the therapeutic and chemopreventive interpretations of these developments.

Characterization of therapy-related acute leukemia in hereditary breast-ovarian carcinoma patients: role of BRCA1 mutation and topoisomerase II-directed therapy.

Therapy-related acute leukemias (t-ALs) represent approximately 10-20% of all acute leukemias, are frequently resistant to chemotherapy, and are associated with guarded outcomes. The national comprehensive cancer network data suggest that t-AL cases are diagnosed at increasing rates in breast cancer patients treated with chemotherapeutic agents targeting topoisomerase II. Two cases of BRCA1-mutated ovarian and breast carcinoma who developed therapy-related APL and ALL, respectively, following topoisomerase II-directed therapy were characterized. Genomic characterization of therapy-related acute promyelocytic leukemia (t-APL) revealed a unique RARA intron 2 breakpoint (Chr17: 40347487) at 3'-end of RARA corroborating breakpoint clustering in t-APL following topoisomerase II inhibition. Both cases of this series harbored germline BRCA1 mutations. The germline BRCA1 mutation in patient with t-APL was detected in exon 8 (HGVS nucleotide: c.512dupT). This mutation in t-APL is extremely rare. Interestingly, t-ALL patient in this series had a BRCA1 mutation (HGVS nucleotide: c.68_69delAG; BIC designation: 187delAG) identical to a previously reported case after the treatment of same primary disease. It is unlikely that two breast cancer patients with identical BRCA1 mutation receiving topoisomerase II-targeted agents for the primary disease developed t-AL by chance. This report highlights the development of t-AL in BRAC1-mutated hereditary breast and ovarian cancer patients and warrants further studies on functional consequences of topoisomerase inhibition in this setting.

[Hereditary breast and ovarian cancer syndrome: Diagnosis and therapeutic implications]. / Syndrome héréditaire de prédisposition au cancer du sein et de l'ovaire : diagnostic et implications thérapeutiques.

Patients who carry the BReast Cancer 1 or 2 (BRCA) gene mutations have an underlying hereditary predisposition for breast and ovarian cancers. These deleterious genetic mutations are the most common ones implicated in hereditary breast and ovarian cancers. Oncogenetic counselling plays a key role in identifying patient for BRCA testing and for mutation identification. BRCA1/2 carriers have to be followed up regularly and may justify breast and/or adnexal prophylactic surgery, according to the French National Cancer Institute guidelines (INCa). Poly- (DNA-riboses) polymerases inhibitors, notably olaparib, have a major role in the management of epithelial ovarian cancer in patients with BRCA mutation and many studies are ongoing to expand their indications in a near future.

A PALB2 truncating mutation: Implication in cancer prevention and therapy of Hereditary Breast and Ovarian Cancer.

Explaining genetic predisposition in Hereditary Breast and Ovarian Cancer (HBOC) families without BRCA mutations is crucial. Germline PALB2 inactivating mutations were associated with an increased risk of HBOC due to its role in DNA repair through cooperation with BRCA proteins. The prevalence and penetrance of PALB2 mutations in Spanish HBOC patients remains unexplained. PALB2 mutation screening has been conducted in 160 high-risk BRCA-negative patients and 320 controls. We evaluated four predicted splicing disruption variants and large genomic rearrangements by multiplex ligation-dependent probe amplification. We have found a frameshift mutation which segregates in an early onset cancer family; and four rare missense variants. None of the variants tested for a predicted splicing disruption showed an aberrant transcript pattern. No large genomic rearrangements were detected. Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population. PALB2 screening may improve genetic counselling through prevention measures, pedigree management and PARP inhibitor therapy selection.

[Molecular Diagnosis and Treatment of HBOC Syndrome].

Hereditary breast and ovarian cancer(HBOC)is an inherited cancer caused by mutations of the BRCA1 or BRCA2 genes. BRCA genetic testing is used for HBOC diagnosis and continues to progress such as the annotation of VUS. In HBOC clinical practice, surveillance methods have been established through collaboration between genetic medicine and cancer medicine, and treatment, including options based on genetic diagnosis, has advanced significantly. Furthermore, the analysis of BRCA1 and BRCA2 function has progressed, and a novel therapeutic method based on synthetic lethality, such as a PARP inhibitor use, has been developed. Furthermore, BRCA genetic testing is going to be used as a PGx test for the selection of sensitive cases. Meanwhile, familial breast cancer and ovarian cancer, in which cases of breast and ovarian cancer accumulate in the family, vary from some patients carrying a single mutated gene, such as BRCA1, to families that have multifactorial predisposing causes. Responsible genes of each group have been identified as high, moderate, and low susceptibility genes, and there are a number of cases where the responsible genes are unknown. Such genes need to be identified and a new diagnostic system needs to be established.

[Diagnosis and Treatment of HBOC Syndrome by a Breast Surgical Oncologist].

Of all breast cancer cases, 5-10% occur because of inherited germline mutation. For hereditary breast and ovarian cancer (HBOC)syndrome, congenital knowledge and strategies for breast cancer treatment and risk reduction are necessary. Regarding the surgical procedure for the cancer site, the ipsilateral breast tumor recurrence rate following breast-conserving surgery in breast cancers with BRCA1/2 mutation is not significantly higher than that in sporadic breast cancers. In addition, prognosis did not differ according to surgical methods. Therefore, breast-conserving surgery for HBOC is not an absolute contraindication, although the risk of developing new primary tumors in the long term should be carefully considered. For the contralateral breast, 3 choices are available, surveillance, chemo-prevention, and risk-reducing mastectomy. Risk-reducing mastectomy is known to decrease the risk of breast cancer by 90%. Genetic counseling is essential for decision making in HBOC treatment. In this review, we reevaluated the current evidence for surgical decision making and systemic therapies for HBOC syndrome.

[Clinical Management of HBOC in Our Hospital].

The cumulative risks of developing epithelial ovarian cancer in women aged 70-75years with BRCA1 and BRCA2 germline mutations are approximately 39-40% and 11-18%, respectively. Here, we present the management of hereditary breast and ovarian cancer(HBOC)in our hospital. HBOC management commences with the selection of appropriate candidates for genetic testing, based on personal and familial characteristics that determine the individual's probability of being a mutation carrier. Pre-test counseling, which is an essential element of genetic counseling, should include discussion of why the test is being offered, how the test results may affect medical management, and the cancer risks associated with the gene mutation. Post-test counseling is also essential; this includes disclosure of the results, discussion of their significance, assessment of their impact on the individual's emotional state, discussion of their impact on the individual's medical management, and how and where the patient will be followed-up. Most women with epithelial ovarian cancer present with advanced-stage high-grade serous carcinoma accompanied by peritoneal dissemination. The absence of reliable early detection methods and the poor prognosis of advanced ovarian cancer have led to the performance of bilateral risk-reducing salpingo-oophorectomy(RRSO) after the completion of childbearing in these women. We performed RRSO procedures for 40 BRCA1/2 carriers. Occult invasive cancer and intraepithelial cancer were not detected. However, 4 cases(10%)showed p53overexpression, which was considered to be a p53 signature. One case of atypical endometrial hyperplasia and 4 cases of atypical glands were diagnosed among the 36 patients who underwent hysterectomy at the time of RRSO. Although no primary peritoneal cancer was diag- nosed after RRSO, surveillance must be continued in these patients.

Trabectedin as a chemotherapy option for patients with BRCA deficiency.

Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

Do Ovarian Cancer Patients with a Family History of Cancer (Suspected BRCA1 or BRCA2 Mutation) Suffer Greater Chemotherapy Toxicity?

OBJECTIVE: Few studies have examined toxicity from potentially curative chemotherapy in ovarian cancer patients at risk for breast cancer susceptibility (BRCA) mutation. METHODS/RESULTS: Ninety-four of the 482 patients appeared at risk for a mutation based on family history and 23 had a confirmed mutation. Hospitalization or emergency department visits were not increased based on family history with odds ratios (95% confidence intervals) of 0.88 (0.52, 1.45) (p =.62) and 0.90 (0.49, 1.58) (p =.71), respectively; similar findings were observed with confirmed mutations. Trends favored improved survival. CONCLUSIONS: Concern for a BRCA mutation should not preclude full dose chemotherapy in ovarian cancer patients treated with curative intent.

Evolution of cancer risk assessment and counseling related to psychological, financial and legal implications.

Cancer risk assessment, genetic counseling and genetic testing have experienced advances and changes over the past two decades due to improved technology, legal movements to protect those at an increased risk for cancer due to genetics, as well as advances in detection, prevention and treatment. This brief article will provide a summary of these advances over three eras of cancer genetics: pre-discovery of the more common high impact genes, namely BRCA1/BRCA2 and the mismatch repair genes associated with Lynch syndrome; the time during which the genes were being discovered; and current day.

Hereditary cancer syndromes: utilizing DNA repair deficiency as therapeutic target.

Human cells have numerous repair mechanisms to counteract various insults incurred on the DNA. Any mutation in these repair mechanisms can lead to accumulation of DNA errors and carcinogenesis. This review aims to discuss the therapeutic options in the two most common DNA repair deficient cancer syndromes, namely Lynch syndrome (hereditary non-polyposis colorectal cancer) and breast cancer susceptibility gene (BRCA) associated ovarian and breast cancer. Deficiency in DNA repair mechanisms renders these tumors with increased sensitivity to platinum agents. There has been increasing amount of information on the utility of the defects in DNA repair as targets for cancer therapy in these syndromes. Novel therapies like poly (ADP-ribose) polymerase (PARP) inhibitors are one of such example where the induction of double stranded breaks in DNA leads to tumoricidal effect in patients with homologous DNA repair deficiency. Interestingly, patients with DNA repair deficiencies tend to have a more favorable prognosis than sporadic malignancies. In microsatellite high colorectal cancer patients, this has been attributed to increased recruitment of CD8+ T lymphocytes in tumor microenvironment. However, these tumors are able to limit the host immune response by activation of immune checkpoints that seem like attractive targets of therapy in the future.

Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome.

Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53).

Systemic therapy options in BRCA mutation-associated breast cancer.

BRCA mutation-associated breast cancers are characterized by deficient homologous recombination of DNA, and 80 % of BRCA1-associated breast cancers display the basal-like molecular subtype. Traditionally, BRCA carriers have received conventional systemic chemotherapy based on their baseline tumor characteristics, and it is generally accepted that after the appropriate treatment the prognosis of a mutation carrier is equivalent to that of a patient with sporadic breast cancer. However, with the growing understanding of the functions of BRCA1/2 proteins in homologous DNA repair, it is recognized that BRCA-associated breast cancer tumors may have distinct biochemical characteristics and thus require tailored treatment strategies. Tumors arising in patients with BRCA mutations were shown to be particularly sensitive to platinum compounds or inhibitors of poly(ADP-ribose) polymerase. In addition, BRCA1-mutation carriers seem to benefit from anthracycline-taxane-containing regimens as much as sporadic triple-negative breast cancers do. In this article, we review the functions of the BRCA1 and BRCA2 genes, and their differential chemosensitivity in both the preclinical and clinical settings. The optimal chemotherapy regimen for this subset of patients still remains to be determined.

Hereditary ovarian cancer: recent molecular insights and their impact on screening strategies.

PURPOSE OF REVIEW: This review will focus on the implications of BRCA status in the patient with high-grade serous ovarian cancer, the differences between BRCA1 and BRCA2 mutations, and the most effective risk-reducing strategies. RECENT FINDINGS: Women with BRCA-associated epithelial ovarian cancer represent a unique group who commonly are diagnosed at a younger age, have advanced high-grade serous disease, have improved sensitivity to platinum-based chemotherapy in both the upfront and recurrent setting, and have an overall improved prognosis. Promising novel therapeutic agents such as poly (ADP-ribose) polymerase inhibitors have increased activity in patients with inherited BRCA mutations and may also have a role in patients with noninherited tumors that have decreased BRCA activity. Risk-reducing salpingo-oophorectomy (RRSO) is effective in decreasing risks of both breast and gynecologic cancer in women with BRCA mutations. However, when counseling women at inherited risk, the inherent phenotypical differences between BRCA1 and BRCA2 mutations must be considered. SUMMARY: Patients with BRCA-associated epithelial ovarian cancer have improved response to platinum-based chemotherapy, improved survival, and may be appropriate candidates for treatment with novel targeted therapies. RRSO remains the most effective risk-reduction strategy in women with BRCA mutations.