Breast cancer incidence in BRCA mutation carriers with ovarian cancer: A longitudal observational study.

OBJECTIVES: We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. METHODS: Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. RESULTS: The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9-90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11-168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. CONCLUSION: The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Temporal trends of subsequent breast cancer among women with ovarian cancer: a population-based study.

PURPOSE: To examine trends, characteristics and outcomes of women who develop both ovarian and breast cancers. METHODS: This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1973 to 2013. Among ovarian cancer (n = 133,149) and breast cancer (n = 1,143,219) cohorts, women with both diagnoses were identified and temporal trends, tumor characteristics and survival were examined. RESULTS: There were 6446 women with both malignancies, representing 4.8% of the ovarian cancer cohort and 0.6% of the breast cancer cohort. Women with ovarian cancer who had secondary breast cancer were younger than those without secondary breast cancer early in the study period (52.3 versus 59.2 in 1973) but older in more recent years (68.5 versus 62.1 in 2013, P < 0.001). The number of breast cancer survivors who developed postcedent ovarian cancer decreased from 1.5 to 0.2% from 1979 to 2008 (relative risk reduction 90.0%, P < 0.05). Similarly, the number of ovarian cancer survivors who developed postcedent breast cancer decreased from 7.2 to 2.0% from 1973 to 2008 (relative risk reduction 72.4%, P < 0.05). Tumor characteristics were more likely to be favorable in women with ovarian cancer who developed postcedent breast cancer but unfavorable in those who had antecedent breast cancer (all, P < 0.05). Women with ovarian cancer who had secondary breast cancer had superior cause-specific survival compared to those who did not develop breast cancer regardless of breast cancer timing (P < 0.05). CONCLUSION: Our study demonstrated that the demographics of women who develop breast cancer and ovarian cancer have changed over time and diagnosis of secondary breast cancer after ovarian cancer has decreased.

Decreasing secondary primary uterine cancer after breast cancer: A population-based analysis.

OBJECTIVE: To report population-based statistics of women with uterine cancer and a history of prior breast cancer. METHODS: This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Temporal trends, clinico-pathological characteristics, and survival of women with uterine cancer who had prior breast cancer were assessed. RESULTS: Among 237,686 women with uterine cancer, 8235 (3.5%) women had antecedent breast cancer. The number of women with uterine cancer who had a history of breast cancer increased between 1975 and 1989 (21.1-fold relative risk-increase, P < 0.001) and then decreased between 1989 and 2013 (relative risk-reduction [RRR] 11.1%, P = 0.008). The number of uterine cancer among breast cancer survivors decreased between 1990 and 2008 (RRR, 86.0%, P < 0.001). Women with uterine cancer and antecedent breast cancer were more likely to be older and white compared to those without a history of breast cancer (P < 0.05). Uterine tumors after breast cancer were more likely to have serous (10.5% versus 5.7%), carcinosarcoma (8.9% versus 4.4%), or clear cell (2.1% versus 1.2%) histology and present with grade 3 (30.8% versus 21.5%) and stage I disease (64.6% versus 62.5%) compared to tumors in women without breast cancer (all, P < 0.05). After propensity score matching, women with uterine cancer after breast cancer were less likely to die from uterine cancer (adjusted-hazard ratio [HR] 0.675) but more likely to die from other malignancies (adjusted-HR 4.090), particularly breast cancer, and had poorer overall survival (adjusted-HR 1.154) compared to those without breast cancer. CONCLUSION: The diagnosis of uterine cancer after breast cancer is decreasing. While uterine tumors following breast cancer are associated with high-risk tumor characteristics, women with uterine cancer after breast cancer are more likely to die from other malignancies.

Efficacy of pegylated liposomal doxorubicin maintenance therapy in platinum-sensitive recurrent epithelial ovarian cancer: a retrospective study.

OBJECTIVE: To examine the effectiveness of pegylated liposomal doxorubicin (PLD) maintenance therapy (intravenous administration at dose 40 mg/m2 on day 1, repeated every 4 weeks) after first-line salvage chemotherapy for platinum-sensitive recurrent epithelial ovarian cancer. METHODS: This retrospective cohort study examined women with a first recurrence of platinum-sensitive epithelial ovarian cancer diagnosed between 2005 and 2015. Eligible cases had PLD maintenance following the first-line salvage chemotherapy (n = 28). Outcomes of interest included adverse events related to PLD maintenance therapy and survival outcome after the first recurrence. RESULTS: The median number of PLD maintenance cycles was 7.5 (range 2-26), and 11 (40%) women received ≥ 12 cycles. The median cumulative dose of PLD was 432.5 mg/m2 (range 120-1200 mg/m2). No women developed cardiotoxicity or secondary malignancies. There were 16 (57%) women who developed any grade of adverse events, including 3 (11%) women who developed grade 3 adverse events. There were no grade 4 adverse events. The most common adverse event was mucositis (n = 7, 25%). Dose reduction due to adverse events occurred in 14 (50%) women including 3 (11%) women with discontinuation due to toxicity. Median progression-free survival and overall survival after the initiation of PLD maintenance was 14.5 months (2-year rate 21.1%) and 51.2 months (5-year rate 43.4%), respectively. CONCLUSION: Our study suggests that PLD maintenance therapy for platinum-sensitive recurrent ovarian cancer is relatively well tolerated with the use of dose reduction to manage toxicity. Our study suggests that PLD maintenance therapy may be effective for women with platinum-sensitive recurrent epithelial ovarian cancer.

Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer.

BACKGROUND AND PURPOSE: Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets. METHODS: This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3+Helios+) and other immune cell subsets were monitored during treatment and compared with healthy controls. RESULTS: Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2-48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naïve Tregs [greater than 2.5 (the median of the naïve Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naïve Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of  %CD4 + Naïve T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40). CONCLUSION: Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naïve Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.

Carboplatin/Paclitaxel Induction in Ovarian Cancer: The Finer Points.

The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials, as well as ongoing trials for which only preliminary results have been published, have fueled debates on the optimal dose and schedule; these have focused not only on weekly vs q3-weeks paclitaxel, but also on other modifications and the advisability of adding bevacizumab. Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available.

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope.

Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of α-smooth muscle actin-expressing stromal cells. Integrin α10ß1 can serve as a receptor for the HU177 epitope in α-smooth muscle actin-expressing stromal cells and subsequently regulates Erk-dependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized α10ß1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors.

Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer.

OBJECTIVES: To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity. METHODS: Recurrent ovarian cancer patients with no limit on prior treatments were eligible. Irinotecan 250mg/m2 (amended to 175mg/m2 after toxicity assessment in first 6 patients) and bevacizumab 15mg/kg were administered every 3weeks until progression or toxicity. Response was assessed by RECIST or CA-125 criteria every 2cycles. RESULTS: Twenty nine patients enrolled (10 were platinum-sensitive and 19 were platinum-resistant). The median number of prior regimens was 5 (range 1-12); 13 patients had prior bevacizumab and 11 prior topotecan. The PFS rate at 6months was 55.2% (95% CI: 40%-77%). The median number of study cycles given was 7 (range 1-34). Median PFS was 6.8months (95% CI: 5.1-12.1months); median OS was 15.4months (95% CI: 11.9-20.4months). In this study, no complete response (CR) was observed. The objective response rate (ORR; PR or CR) for all patients entered was 27.6% (95% CI: 12.7%-47.2%) and the clinical benefit rate (CR+PR+SD) was 72.4% (95% CI: 52.8%-87.3%); twelve patients experienced duration of response longer than 6months. In the 24 patients with measurable disease, a partial response (PR) was documented in 8 (30%) patients; 13 patients maintained stable disease (SD) at first assessment. The most common grade 3/4 toxicity was diarrhea. No treatment-related deaths were observed. CONCLUSIONS: Irinotecan and bevacizumab has activity in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.

An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: An NRG Oncology/Gynecologic Oncology Group experience.

PURPOSE: We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC). METHODS: We reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous). RESULTS: There were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p<0.001). After adjusting for age and stratifying by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR=1.53 (1.33, 1.76; p<0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly Paclitaxel versus observation in OCCC compared to SOC (p=0.048). CONCLUSIONS: This is one of the largest analyses to date of OCCC treated on multiple cooperative group trials. OCCC histology is more common than SOC in early stage disease. When adjusted for prognostic factors, in early stage patients, PFS was better for OCCC than for SOC; however, in late-stage patients, OCCC was significantly associated with decreased OS. Finally, treatment effect was influenced by histology.

Primary large cell neuroendocrine carcinoma of the breast, a case report with an unusual clinical course.

Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34-years-old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline-containing neo-adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo-adjuvant chemotherapy, the patient underwent breast-conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo-adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options.

Continuous-infusion topotecan and erlotinib: a study in topotecan-pretreated ovarian cancer assessing shed collagen epitopes as a marker of invasiveness.

BACKGROUND: Continuous-infusion topotecan with erlotinib has the potential to reverse topotecan resistance due to drug efflux mechanisms. We assessed the activity of such a regimen in ovarian cancer patients previously failing bolus topotecan. Assay for shed collagen epitopes recognized by antibody HU177 during treatment explored its ability to reflect tumor invasion. METHODS: Topotecan 0.4 mg/m(2) per day was administered by continuous infusion for 9-10 days every 3 weeks. Erlotinib, 150 mg orally, was administered on days 1-10 of each cycle. Cycles were repeated until progression or toxicity. Serum for shed HU177 collagen epitopes was collected weekly. This was a two-stage design to detect a CA-125 response rate of at least 20% in 30 patients after completing two treatment cycles. The trial would be terminated early if there were less than two CA-125 responses in 16 patients. Four or more CA-125 responses in 30 patients would justify further study of this regimen in prior topotecan treatment failures. RESULTS: Six patients were enrolled, with four receiving three or more cycles and one achieving a partial response by cancer antigen 125 (CA-125) criteria. Shed epitope levels became undetectable on at least one measurement in all patients who received three or more cycles (Fig. 1A) and reappeared concomitantly with rises in CA-125 and clinical progression (Fig. 1B). After logistical delays, the trial was closed by the sponsor's decision to stop developing erlotinib in ovarian cancer. FIGURE 1: Monitoring of combination treatment. A, B, C, D, and F refer to patients. (A):: Topotecan and erlotinib. (B):: CA-125 in units/mL. CONCLUSION: Continuous-infusion topotecan with erlotinib was found safe in six pretreated ovarian cancer patients; one met CA-125 criteria for partial response. Serial shed epitope levels to reflect invasiveness deserve further study.

Chronic thalidomide and chemoembolization for hepatocellular carcinoma.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) has been used to curtail tumor vasculature and delay tumor progression in hepatocellular carcinoma (HCC). We conducted a phase I trial to evaluate the efficacy and toxicity of thalidomide when combined with TACE in patients with advanced HCC. METHODS: Between June 2000 and November 2003, 56 patients with unresectable HCC and amenable to TACE were enrolled. The starting dose of thalidomide was 200 mg/day and was escalated every 2 weeks as tolerated to a maximum dose of 1,000 mg/day. Dose reductions and discontinuation were determined by toxicity. TACE was performed 4 weeks after initiation of thalidomide therapy and repeated as necessary. RESULTS: Overall, 47 and 55 patients were evaluable for response and toxicity, respectively; the median dose of thalidomide given was 200 mg/day. Three patients (6.38%) patients achieved complete responses, whereas 10 (21.3%) had partial responses, for an overall response rate of 27.7%, and 27 (57.5%) had stable disease. Median progression-free survival was 7 months (95% confidence interval [CI]: 5-10 months), and median OS was 21 months (95% CI: 16-28 months) (Fig. 1). Fatigue and lethargy (49.1%), constipation (47.3%), and nausea (43.6%) were common. Grade 3-4 toxicities consisted mostly of increased aspartate aminotransferase (43.6%) and elevated alanine aminotransferase (38.2%) (Table 1). CONCLUSION: Thalidomide and TACE were commonly associated with nonhematologic side effects, with fatigue and constipation being prominent. With a lack of clear therapeutic benefit, this combination is unlikely to be pursued for HCC.

Ovarian cancer: a brief historical overview of intraperitoneal trials.

The standard platinum-based treatment of previously untreated advanced ovarian cancer continues to evolve because despite high response rates to such first-line treatment, a majority of patients will experience relapse. For many years, the optimal treatment for women with advanced ovarian cancer has been maximum cytoreductive surgery followed by intravenous (IV) platinum and taxane chemotherapy. Later, several randomized multicenter phase III clinical trials demonstrated that intraperitoneal (IP) chemotherapy was superior to standard IV chemotherapy when there was minimal residual disease after primary debulking surgery. The underlying rationale for use of IP therapy is based on the dose-effect relationship for platinum drugs in ovarian cancer. However, barriers to implementation of IP therapy in the routine clinical setting include concern for toxicity, tolerability of planned treatment, and catheter-related complications. In this article, we highlight the key trials and recent directions in IP therapy of ovarian cancer and briefly discuss another approach to the delivery of IP chemotherapy, known as hyperthermic intraperitoneal chemotherapy.

Ovarian cancer in BRCA mutation carriers: improved outcome after intraperitoneal (IP) cisplatin.

BACKGROUND: Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. METHODS: Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. RESULTS: Ten patients that were confirmed to have BRCA mutations-all with high-grade and stages IIC to IV disease-survived a median of 10 years (range: 4-18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. CONCLUSIONS: This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

Targeting HER2 in ovarian and uterine cancers: challenges and future directions.

Targeting the human epidermal growth factor receptor 2 (HER2) has yielded major advances in breast cancer treatment. Accordingly, it has generated interest in targeting HER2 to treat gynecologic malignancies. Multiple studies have evaluated the rates of HER2 overexpression and/or amplification in ovarian and uterine cancers. HER2 has also been studied as a prognostic factor but resulting data has been contradictory. Moreover, clinical trials of HER2-directed therapies, including trastuzumab, pertuzumab, and lapatinib in ovarian and uterine cancers have been largely disappointing. Current research on HER2 in gynecologic malignancies has focused on identifying mechanisms of resistance and looking further into how HER2 signaling in gynecologic cancers differs from breast cancer. In this review, we highlight the existing data of targeting HER2 in ovarian and uterine carcinomas, many dating back more than a decade, and discuss future directions in pursuing HER2 as a potential target in these diseases.

Novel taxanes.

Since their addition to paclitaxel in the oncologists' armamentarium in the early 1990s, several new taxane formulations have been developed. Besides docetaxel and nab-paclitaxel, new analogs with better therapeutic profiles are being investigated. The goals of this next generation of taxanes are to improve the toxicity profile and efficacy, and to overcome resistance patterns. Several new taxanes, including cabazitaxel, paclitaxel poliglumex, paclitaxel+endotag, and polymeric-micellar paclitaxel, have shown clinical efficacy. These chemotherapeutics are part of many ongoing phase II and III studies on various cancer types. In addition, there are immunotoxins that link key antibodies to mitotic spindle inhibitors (trastuzumab emtansine and brentuximab vedotin). Through this mechanism, novel formulations increase cytotoxicity, improve specificity, and create possibilities for drug enhancement.

Clinical features of taxane neuropathy.

Sensory neuropathy is the dose-limiting toxicity of paclitaxel and also impacts on the use of docetaxel and other taxanes. The cause of this adverse effect has to do with their mechanism of action against microtubules and its interaction with neuronal cytoskeletal components. The variability of this toxicity is defined by several factors including disease type, taxane class, schedule and dose of the specific drug, patient demographics, and use of taxanes in combination regimens (especially with the platinums that are also neurotoxic). Prevention of life-long neuropathy is only produced if the causative drug is halted--treatments to reverse toxicity have shown only minimal improvement. This review investigates trials defining the clinical factors that determine the therapeutic window of taxanes and the enhanced susceptibility to this toxicity. In addition, case vignettes illustrate the range of clinical manifestations of this toxicity during taxane administration.

The effect of germ-line BRCA mutations on response to chemotherapy and outcome of recurrent ovarian cancer.

OBJECTIVE: The treatment of recurrent epithelial ovarian cancer (rEOC) remains a major challenge because of the development of platinum resistance. To identify treatment regimens associated with better outcomes in BRCA mutation carriers compared with patients with nonhereditary (NH) disease, we summarized the experience after chemotherapy treatment of rEOC in 1 institution and compared the outcome in BRCA mutation carriers versus NH subsets. METHODS: We retrospectively analyzed 256 patient records with rEOC who were treated with second-, third-, and fourth-line treatment with the usual sequential regimens consisting of either pegylated liposomal doxorubicin (PLD), taxanes, gemcitabine, or topotecan (alone or in combination with platinum) between 2002 and 2012 at our institution. The analysis of founder mutations in 8 hotspots was performed. The outcome in BRCA mutation carriers was compared with that of patients with NH disease. RESULTS: BRCA mutation carriers treated with PLD (with or without platinum) or with gemcitabine + platinum had improved progression-free survival (PFS) and a lower risk for disease progression (adjusted for age, line of treatment, and platinum sensitivity) compared with patients with NH disease. By contrast, treatment with taxanes (with or without platinum) or topotecan led to similar PFS in BRCA mutation carriers and in patients with NH disease. Under all treatment regimens, BRCA mutation carriers showed improved overall survival after adjusting for age, line of treatment, and platinum sensitivity. CONCLUSIONS: This single-institution experience provides indications of an enhanced benefit in PFS for BRCA mutation carriers compared with patients with NH disease across a number of drug regimens (PLD, platinum, or gemcitabine + platinum) regardless of platinum sensitivity and line of therapy.