Vanda Salutari

Lifestyle and environmental factors in women carrying BRCA pathogenic variants with and without cancer

Abstract Background In the development of breast cancer and ovarian cancer there may be an influence of lifestyle and environmental factors. This influence could be relevant also in patients with genetic predisposition such as in carriers of germline pathogenic variants in the BRCA genes. However, this issue has been addressed in only a few studies so far. Methods In this retrospective, multicenter case-control study, we enrolled participants with a pathogenic variant BRCA gene and divided into 2 groups: group 1, patients with breast cancer and/or ovarian cancer, and group 2, subjects without cancer. We compared these groups regarding demographic data as age, body mass index, smoking habits, estroprogestinic use, Mediterranean diet, and physical activity. Multivariable analyses were used to identify predisposing factors. All evaluations were 2-tailed and considered statistically significant if the P value was less than .05. Results We enrolled 281 participants, 135 (79.4%) with breast cancer, 32 (18.8%) with ovarian cancer, 3 (1.8%) with both, and 111 unaffected (39.5%) women. Independent risk factors associated with cancer were age (P < .0001); body mass index (P = .007); family history (P = .002); occupation (P = .003); smoking habits (P = .012), number of cigarettes smoked (P = .016), and pack-year index (P = .022); and estroprogestinic use (P = .032) and years of estroprogestinic use (P = .029). At multivariate analysis, age (odds ratio [OR] = 1.062; P < .0001), family history (OR = 0.129; P = .001), number of cigarettes smoked (P = .014), and estroprogestinic use (OR = 2.009; P = .025) were statistically significant risk factors associated with cancer development. Conclusions In the development of breast cancer and ovarian cancer, lifestyle and environmental factors seem to play a statistically significant role in the presence of genetic predisposition associated with BRCA1 and BRCA2 gene mutations.

Hyperthermic Intraperitoneal Chemotherapy in Platinum-Sensitive Recurrent Ovarian Cancer: A Randomized Trial on Survival Evaluation (HORSE; MITO-18)

PURPOSE To investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to secondary cytoreductive surgery (SCS) without neoadjuvant chemotherapy has a benefit on progression-free survival (PFS), as opposed to SCS alone in patients with platinum-sensitive recurrent epithelial ovarian cancer (platinum-free interval, >6 months). METHODS This was a multicenter randomized phase III study. Random assignment was performed at the time of surgery in cases with residual tumor ≤0.25 cm. HIPEC with cisplatin (CDDP) 75 mg/m 2 for 60 minutes at 41.5°C was administered at the end of surgery in the experimental arm. Both groups received postoperative platinum-based chemotherapy. The primary end point was PFS. The safety profile and postrecurrence survival (PRS) were the secondary end points. RESULTS A total of 167 patients underwent random assignment, 82 patients to SCS plus HIPEC (experimental arm) and 85 to SCS alone (control arm). The median follow-up was 83 months (IQR, 64-102). The median PFS was 23 months (95% CI, 17 to 29) in the group that underwent surgery alone and 25 months (95% CI, 18 to 32) in the group that underwent cytoreductive surgery with HIPEC. The probability of PRS at 5 years was 61.6% (95% CI, 50.8 to 72.4) in the SCS group and 75.9% (95% CI, 66.5 to 85.3) in the SCS plus HIPEC group. The incidence of postoperative adverse events of any grade was similar between the two groups. CONCLUSION The addition of HIPEC to complete or nearly complete primary SCS did not confer a benefit in terms of PFS in patients with platinum-sensitive peritoneal recurrence.

ADAGIO: A Phase IIb, Open-Label, Single-Arm, Multicenter Study Assessing the Efficacy and Safety of Adavosertib (AZD1775) as Treatment for Recurrent or Persistent Uterine Serous Carcinoma

PURPOSE This phase IIb, single-arm, multicenter, global study (ADAGIO; ClinicalTrials.gov identifier: NCT04590248 ) assessed the efficacy and safety of adavosertib in patients with recurrent/persistent uterine serous carcinoma (USC) who had previously received platinum-based chemotherapy. METHODS Eligible patients were age 18 years and older and had histologically confirmed recurrent/persistent USC, previously treated with at least one platinum-based chemotherapy regimen, and with evidence of measurable disease. Adavosertib was administered orally at 300 mg once daily on days 1-5 and 8-12 of a 21-day cycle until discontinuation criteria were met. The primary end point was objective response rate (ORR) by blinded independent central review (BICR). Secondary end points included duration of response (DoR), progression-free survival (PFS), safety, and tolerability. Biomarkers previously associated with adavosertib response in other settings were assessed in archival tissue samples. RESULTS In 104 evaluable patients, one complete response and 26 partial responses were observed, for an ORR by BICR of 26.0% (95% CI, 17.9 to 35.5). Median DoR was 4.7 months (95% CI, 3.8 to 8.3); median PFS was 2.8 months (95% CI, 2.6 to 3.9). Biomarker analysis identified no single predictive alteration for adavosertib response, although a trend was observed for CCNE1 amplification or high cyclin E1 protein expression. Most patients (97.2%) experienced treatment-related adverse events (TRAEs), most frequently diarrhea (59.6%), nausea (59.6%), and anemia (58.7%). Grade ≥3 TRAEs occurred in 60.6% of patients, with neutropenia (21.1%) and fatigue (13.8%) most common. 17.4% of patients discontinued adavosertib due to AEs (treatment-related in 14.7%). CONCLUSION Adavosertib showed some antitumor activity in patients with recurrent/persistent USC. However, at 300 mg once daily dosing, it was not well tolerated in this population. Exploratory biomarker studies suggest CCNE1 /cyclin E1 expression may enrich for response to Wee1 inhibition in USC.

Hormone replacement therapy in gynecological cancer survivors and BRCA mutation carriers: a MITO group survey

Early iatrogenic menopause in gynecological cancer survivors and BRCA mutation (BRCAm) carriers undergoing risk-reducing salpingo-oophorectomy (RRSO) is a major health concern. Hormone replacement therapy (HRT) is the most effective remedy, but remains underused in clinical practice. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) group promoted a national survey to investigate the knowledge and attitudes of healthcare professionals regarding the prescription of HRT. The survey consisted of a self-administered, multiple-choice 45-item questionnaire, available online to all MITO members for 2 months starting from January 2022. A total of 61 participants completed the questionnaire (47 out of 180 MITO centers; compliance: 26.1%). Most respondents were female (73.8%), younger than 50 years (65.6%), and gynecologic oncologists (55.7%), working in public general hospitals (49.2%). An 84.4% of specialists actively discuss HRT with patients and 51.0% of patients ask the specialist for an opinion on HRT. The rate of specialists globally in favor of prescribing HRT was 22.9% for ovarian cancer, 49.1% for cervical cancer, and 8.2% for endometrial cancer patients. Most respondents (70.5%) believe HRT is safe for BRCA-mutated patients after RRSO. Nearly 70% of physicians prescribe systemic HRT, while 23.8% prefer local HRT. Most specialists recommend HRT for as long as there is a benefit and generally for up to 5 years. Real-world data suggest that many healthcare professionals still do not easily prescribe HRT for gynecological cancer survivors and BRCA mutation carriers after RRSO. Further efforts are required to implement the use of HRT in clinical practice and to support both clinicians in recommending HRT and patients in accepting it.

Hyperthermic Intra-peritoneal Chemotherapy (HIPEC) in Ovarian Cancer Recurrence

The purpose of this study is to determine the role of surgery followed by hyperthermic intra-peritoneal chemotherapy (HIPEC) versus surgery alone in patients with platinum-sensitive first recurrence of ovarian cancer. Moreover it is a prospective randomized multicenter trial, aimed to investigate the prognostic role of surgery plus HIPEC versus surgery alone in terms of progression free interval, overall survival, morbidity and mortality, second recurrence pattern, quality of life with EORTC QLQ-C30 and QLQ OV28 questionnaires.