Elisabetta Razzaboni

Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes

More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development of molecular diagnostic strategies and targeted therapeutic approaches. The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyze multiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

A rapid genetic counselling and testing in newly diagnosed breast cancer is associated with high rate of risk-reducing mastectomy in BRCA1/2-positive Italian women

BACKGROUND Risk-reducing mastectomy (RRM) decreases breast cancer (BC) risk in BRCA1/2 mutation carriers by up to 95%, but the Italian attitude towards this procedure is reluctant. PATIENTS AND METHODS This is an observational study with retrospective design, using quantitative and qualitative research methods, aimed at evaluating the attitude towards RRM by rapid genetic counselling and testing (RGCT), at the time of BC diagnosis, compared with traditional genetic counselling and testing (TGCT), after previous BC surgery. Secondary aims were to investigate patient satisfaction after RRM and the rate of occult tumour in healthy breasts. A total of 1168 patients were evaluated: 1058 received TGCT, whereas 110 underwent RGCT. RESULTS In TGCT, among 1058 patients, 209 (19.7%) mutation carriers were identified, with the rate of RRM being 4.7% (10 of 209). Conversely in RGCT, among 110 patients, 36 resulted positive, of which, 15 (41.7%) underwent bilateral mastectomy at the BC surgery time, showing an overall good satisfaction, measured by interpretative phenomenological analysis 12 months after the intervention. CONCLUSIONS Our study shows that RGCT in patients with a hereditary profile is associated with a high rate of RRM at the BC surgery time, this being the pathway offered within a multidisciplinary organization.

The impact of reproductive life on breast cancer risk in women with family history or BRCA mutation

Reproductive history and exogenous hormonal exposures are acknowledged risk factors for breast cancer in the general population. In women at increased breast cancer risk for genetic predisposition or positive family history, data regarding these risk factors are limited or conflicting, and recommendations for these categories are unclear. We evaluated the characteristics of reproductive life in 2522 women at increased genetic or familial breast cancer risk attending our Family Cancer Center. Breast cancers in BRCA mutation carriers were more likely to be hormone receptor negative, diagnosed at 35 years or before and multiple during the lifetime than tumors in women at increased familial risk, while the distribution of invasive cancers and HER2 positive tumors was similar in the different risk groups. At least one full-term pregnancy (HR 0.27; 95% CI 0.12–0.58; p = 0.001), breastfeeding either less (HR 0.24; 95% CI 0.09–0.66; p = 0.005) or more (HR 0.25; 95% IC 0.08–0.82; p = 0.022) than one year and late age at menopause (HR 0.10; 95% CI 0.01–0.82; p = 0.033) showed to be protective factors in BRCA mutation carriers, while in women at increased familial risk early age at first full-term pregnancy (HR 0.62; 95% IC 0.38–0.99; p = 0.048) and late menarche (HR 0.61; 95% CI 0.42–0.85; p = 0.004) showed to be the main protective factors. Finally, for the entire population, combined hormonal contraceptives demonstrated to do not increase breast cancer risk. The results of our study suggest that women at high familial risk and mutation carries develop tumors with different clinical-pathological characteristics and, consequently, are influenced by different protective and risk factors.

What about prophylactic surgery in BRCA1/BRCA2 mutation carriers? Observations from an Italian pilot study

To the Editor: BRCA1/2 and other gene mutations are significantly associated to high risk of breast and ovarian cancer. Prophylactic mastectomy and salpingo-oophorectomy are effective risk-reducing surgical options that strongly impact women’s life and their health care needs. Management of BRCA mutation carriers is in constant evolution and reflects the position of different worldwide health care systems. Investigations about women’s experience are needed in Southern European Countries. We developed a pilot anonymous self-reported questionnaire based on literature data and clinical experience of three Breast Centers in Northern Italy to carry out a preliminary study about experiences and opinions of Italian BRCA1/2 mutation carriers on riskreducing surgery. We applied the questionnaire with informed consent to consecutive female BRCA1/2 mutation carriers during a workshop organized by national voluntary associations in November 2015. Closed (categorical) and rating-scale answers were included in a data base and descriptive statistics were carried out. We also requested feedback through open questions that were analyzed qualitatively to identify focused issues. Twenty-nine questionnaires (response rate 72.5%) were collected. Participants were from the Northern (72.4%), the Central (13.8%) and the Southern (13.8%) of Italy: the mean age was 38.2 years (SD 6.7). Twenty-two patients (75.9%) have had a cancer (90.9% breast, 0% ovarian, 9.1% other). The mean age was 34.9 years at first diagnosis (SD 7.4) and 34.4 years at time of genetic testing (SD 7.9). In 65.5% of cases, the respondent was the family index case. Twenty-three (79.3%) patients underwent riskreducing mastectomy at a mean age of 36.3 years (SD 7.1); eight (27.6%) patients had risk-reducing salpingo-oophorectomy at a mean age of 44 years (SD 5.6) of whom seven patients (24.1%) had received both interventions. Five women were in the waiting list for scheduling a risk-reducing procedure. Response rates are reported for each question (some questionnaires were incomplete). Regarding reasons for risk-reducing surgery, women (n=24) reported desire to: avoid having cancer again, reduce the chances of having a first cancer, and avoid living distressing events experienced within the family in the past. Another incentive reported was the prospect of a longer life permitting either childbearing or also the upbringing of children. Risk-reducing mastectomy and salpingo-oophorectomy were considered better options than surveillance-only programs in six (20.7%) respondents Among women who underwent mastectomy (n=23), 13% spontaneously underlined the importance of being able to openly speak with physicians in order to obtain adequate information enabling a suitable discussion. Twenty-four women underwent prophylactic surgery and expressed satisfaction with the decision regarding the procedure, and that they would repeat it to reduce their cancer risk. Risk-reducing surgery decreased subjective worries of developing an oncological disease in most patients (mastectomy 90.9%, n=22; salpingooophorectomy 100%, n=8). An open section of the questionnaire revealed that the event of risk-reducing surgery made women more aware of their own aims and life projects. That is, this kind of preventive intervention produced changes in term of thinking and re-evaluating lifestyle and habits (45.8%; n=24), focus on improving well-being, better organize their work, increase exercise habits and look for a healthier diet. Patients complaint of changes in breast and body sensitivity (ie, loss of skin sensitivity, presence of the prosthesis as a foreign body) after mastectomy (39.1%; n=23) and menopause signs and symptoms linked to salpingo-oophorectomy (37.5%; n=8). Patients reported that risk-reducing surgery (n=24) affects selfperception (24.1%), fears about partner’s perceptions (17.2%) and sexuality (70.8%). Twenty-three women (95.8%, n=24) reported having received positive support from their own families. Conversely, 11 (45.8%, n=24) women complained of attempts to discourage their decision for risk-reducing surgery by health professionals (ie, general practitioner, general surgeon, breast specialist, geneticist, psychologist), with resulting distress, sense of guilt, and the perception that their needs were not taken seriously. Our preliminary data agree with other reported findings about women experiencing prophylactic surgery: Moreover, negative emotional and psychosocial implications linked to self-perceived discouraging attempts from healthcare professionals have been reported. High-risk women ask healthcare professionals for guidance; however, many women have already chosen their preference before consulting a care provider. These preliminary observations underline that psychosocial and emotional aspects need to be addressed by a multi-disciplinary team, enhancing the presence of the psycho-oncologist and breast care nurses. Future projects are needed to thoroughly investigate psychosocial and psychiatric implications of women receiving risk-reducing surgery. DOI: 10.1111/tbj.12825