Prophylactic Salpingo-Oophorectomy and Survival After BRCA1/2 Breast Cancer Resection.

Importance: Few studies have investigated whether prophylactic salpingo-oophorectomy (PSO) for patients with previously resected breast cancer who carry pathogenic germline BRCA1 or BRCA2 variants is associated with a reduced risk of cancer-specific death. Objective: To assess the association of PSO and prophylactic mastectomy (PM) with prognosis after quadrantectomy or mastectomy as primary treatment for patients with BRCA1 or BRCA2 breast cancer. Design, Setting, and Participants: This retrospective cohort study was performed in a single-institution, tertiary referral center. Consecutive patients with invasive breast cancer treated surgically between 1972 and 2019 were recruited and followed up prospectively after they were found to carry the BRCA1 or BRCA2 gene variant. The data analysis was performed between April 2022 and July 2023. Exposure: Following breast surgery, some patients underwent PSO, PM, or both, whereas others did not. Main Outcomes and Measures: The primary study end point was overall survival as measured by the Kaplan-Meier method. Secondary end points were crude cumulative incidence of breast cancer-specific mortality, ipsilateral breast tumor recurrence (IBTR), contralateral breast cancer, ovarian cancer, and ovarian cancer-specific mortality. Results: Of 480 patients included in the cohort (median age at initial surgery, 40.0 years; IQR, 34.0-46.0 years), PSO was associated with a significantly reduced risk of death (hazard ratio [HR], 0.40; 95% CI, 0.25-0.64; P < .001). This reduction was most evident for patients carrying the BRCA1 variant (HR, 0.35; 95% CI, 0.20-0.63; P = .001), those with triple-negative disease (HR, 0.21; 95% CI, 0.09-0.46; P = .002), and those with invasive ductal carcinoma (HR, 0.51; 95% CI, 0.31-0.84; P = .008). Prophylactic salpingo-oophorectomy was not associated with risk of contralateral breast cancer or IBTR. Initial or delayed PM was associated with a reduced risk of IBTR but not with overall survival or breast cancer-specific mortality. Conclusions: The study findings suggest that PSO should be offered to all patients with BRCA1/2 breast cancer who undergo surgery with curative intent to reduce risk of death. In particular, PSO should be offered to patients with the BRCA1 variant at the time of breast surgery.

Incidental carcinomas in prophylactic specimens in BRCA1 and BRCA2 germ-line mutation carriers, with emphasis on fallopian tube lesions: report of 6 cases and review of the literature.

The identification of germ-line mutations in 2 genes (BRCA1 and BRCA2) responsible for the majority of hereditary ovarian cancers has led an increasing number of women carriers of these mutations to undergo prophylactic oophorectomy (PO) to reduce their risk of subsequent ovarian carcinoma. A large number of unexpected, clinically occult neoplasms are thus being discovered. Up to December 2004, the Medical Genetics Service of the National Cancer Institute in Milan, Italy, has tested 756 probands from breast and/or ovarian cancer families for BRCA1 and BRCA2 germ-line mutations. Molecular screening of family members led to the identification of 344 female carriers of BRCA1 (239) or BRCA2 (105) germ-line mutations. Of the 186 potentially eligible women (37 of whom had tested positive for BRCA1 and 13 for BRCA2 mutation), 50 (26.8%) chose to undergo PO. Six clinically occult primary gynecologic malignancies (2 stage IIIC serous carcinomas of the ovary, 3 in situ serous carcinomas of the fallopian tube, and 1 stage IIB invasive serous carcinoma of the fallopian tube) and 1 occult ovarian metastasis from breast carcinoma were identified in the PO specimens of 7 women (all BRCA1 mutated). Four of the patients with occult primary gynecologic cancers are alive without disease 129, 87, 38, and 7 months after PO, respectively. One of the 2 patients with primary ovarian cancer and the single patient with tubal invasive carcinoma are alive with recurrent disease 83 and 20 months after PO, respectively. In addition, one of the patients whose PO specimen did not show any malignancy presented with stage IIIC tubal carcinoma 77 months after PO. The relatively high number of tubal neoplasms found at PO in this group of patients underlines the linkage between mutation and the risk of developing tubal cancer, and stresses the need to include removal of the entire tubes at the time of PO and of thoroughly evaluating the specimens at the microscopic level. The upstaging of all 3 invasive carcinomas after staging surgery, and the late recurrence and persistence of 2 of them despite treatment indicate that small size of the tumors should not preclude therapy.

Type II versus Type III nerve-sparing radical hysterectomy: comparison of lower urinary tract dysfunctions.

OBJECTIVES: According to our previous experience, Type III Nerve-sparing Radical hysterectomy (NSRH) for cervical cancer presented an acceptable urologic morbidity, without compromising radicality. The aim of this study was to compare Type NSRH with other types of RH in terms of incidence of early bladder dysfunctions and perioperative complications. METHODS: One hundred and ten patients with cervical cancer were submitted to Type II RH (group 1), Type III NSRH (group 2) and Type III RH (group 3). We assessed the postoperative early bladder function and complications. The follow-up period was 3 months. RESULTS: Group 1 had a significantly shorter duration of the surgery, minor mean blood loss and shorter mean length of postoperative stay when compared to groups 2 and 3. No intraoperative complications were reported in either of the groups. The groups did not differ significantly in terms of GIII/IV morbidity (group 1 = 10%, group 2 = 10% and group 3 = 15%, chi(2), P value: 0.65). Not even they differed in terms of urologic GI-IV morbidity (group 1 = 13%, group 2 = 15% and group 3 = 10%, chi(2), P value = 0.88). Groups 1 and 2 presented a prompt recover of bladder function, significantly different from that of group 3. There was a significant difference between the groups regarding the number of patients discharged with self-catheterism (group 1 = 0; group 2 and group 3 = 11; chi(2), P value << 0.05). CONCLUSIONS: The Type III NSRH seems to be comparable to Type II RH and superior to Type III RH in terms of early bladder dysfunctions.

MRI in the early detection of breast cancer in women with high genetic risk.

AIMS AND BACKGROUND: Women with BRCA1 or BRCA2 germline mutations have an elevated risk of developing breast and/or ovarian cancer. Because of the early onset of the disease, screening of this group of women should start at an earlier age than in the general population. The association of breast magnetic resonance imaging (BMRI) and ultrasonography (US) with mammography (MX) and clinical breast examination (CBE) in the regular surveillance of these individuals has been proposed and seems to improve the early detection of breast cancer. METHODS: Within a multicenter study started by the Istituto Superiore di Sanità (Rome), at the Istituto Nazionale Tumori of Milan (INT) we enrolled 116 women at high genetic risk for breast cancer; they were either BRCA1 or BRCA2 mutation carriers or had a strong family history of breast cancer. They underwent CBE, MX, US and BMRI once a year. RESULTS: Between June 2000 and April 2005, at INT 12 cancers were detected among the 116 screened individuals (10%). In this subgroup, 1 patient refused BMRI and in 2 cases US was not performed. With BMRI we found 11 cancers and 6 of them were detectable only by this technique. In these 6 cases, the size of the disease was less than 1 cm and MX was false negative due to irregularly nodular parenchyma in 4 cases and scar tissue or prosthesis in the other 2. US was not performed in 2 cases and was false negative in 4 cases. Three false positive results were found with BMRI: 1 case was considered suspect but related to hormonal influences; 1 case with the same pattern was sent for second-look US, which gave a negative result and BMRI review after 6 months showed normalization of the parenchyma; in the third case histology revealed the presence of adenosis. No false positive results were registered for MX. CONCLUSIONS: The aim of secondary prevention is the detection of cancer at its earliest stage. BMRI screening in women with BRCA1 or BRCA2 mutations or at high familiar risk appears to be highly sensitive and may detect mammographically occult disease. The accuracy of MR imaging is higher than that of conventional imaging but the technique is flawed by a lower specificity. In order to avoid unnecessary biopsies we believe that the combination of BMRI and conventional imaging can be very useful in screening women with a high genetic risk of breast cancer, especially with second-look evaluation by means of US when BMRI yields the only positive diagnostic result. Second-look US has been demonstrated to be of critical importance both in recognizing false positive BMRI results and in guiding biopsies, when necessary.

Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers.

Although growing numbers of tubal carcinomas in carriers of BRCA1 and BRCA2 germline mutations have been reported, very little is known about the nature and frequency of their possible precursor lesions. The aim of this study is to investigate the occurrence of atypical proliferative tubal lesions in grossly normal fallopian tubes from 26 women with BRCA1 and BRCA2 germline mutations who underwent prophylactic salpingo-oophorectomy and whose ovaries were histologically negative for carcinoma. Fallopian tubes from 49 women who had undergone hysterectomy with salpingo-oophorectomy for uterine leiomyoma served as controls. In the 22 BRCA1-mutated women, there were two in situ carcinomas and two atypical hyperplasias of the tubal epithelium. The tubes of the BRCA2-mutated women and of the 49 control women did not show any atypical proliferation. The frequency of proliferative lesions of the tubal epithelium, including in situ carcinoma, appears to be increased in BRCA1 mutation carriers. Removal and thorough examination of the fallopian tubes at the time of surgical prophylaxis for ovarian cancer is therefore recommended.

Gemcitabine combined with oxaliplatin (GEMOX) as second-line chemotherapy in patients with advanced ovarian cancer refractory or resistant to platinum and taxane.

OBJECTIVES: The aim of this multicenter feasibility study was to determine the toxicity profile and antitumor activity of the gemcitabine plus oxaliplatin combination as second-line treatment in platinum plus paclitaxel resistant/refractory advanced ovarian cancer. METHODS: Twenty patients received a 30-60-min infusion of gemcitabine a week for 2 weeks, followed by 120-180 min infusion of oxaliplatin every 3 weeks. The doses used were 1,000 and 130 mg/m(2), respectively. Seventeen cases (85% of the total) were platinum resistant and 3 (15%) were platinum refractory. RESULTS: Grade 3/4 thrombocytopenia occurred in 14/20 of cases (70%); there were no symptomatic cases. 2 patients required platelet transfusion and 8 patients received hydrocortisone. The dose- limiting toxicity was thrombocytopenia. Combined grade 3/4 neutropenia was observed in 8/20 (40%) of cases (no sepsis was registered). Five patients were treated with recombinant erythropoietin because of grade 3 anemia and 4 cases received G-CSF prophylactically from the first cycle. The overall response rate of the combination in terms of antitumor activity was 26% (95% CI = 9-51%). CONCLUSION: A combination of gemcitabine and oxaliplatin using this schedule gave rise to a moderate/severe toxicity profile and would be feasible only if growth factors were used and/or gemcitabine were administered at lower doses. The antitumor activity of the combination was insufficient reward for the resultant toxicity profile. However, equivalent to that of other drugs used in platinum refractory and resistant patients.

Microinvasive squamous cell cervical carcinoma.

Several histologic tumor-related features are the key factors for further treatment planning in microinvasive cervical cancer (MIC) after conization. To better define the indications for conservative treatment of MIC we conducted a literature review for prognostic factors for MIC and we carried out a prospective observational study evaluating most important pathologic factors and the relationships between tumor and edges of the cone and incidence of recurrences. In our experience seven recurrences were observed. Two distinct groups of patients were identified with a clearance lower or higher of 10 and 8 mm for apical and lateral margin respectively. Depth of infiltration and even lymph-vascular involvement have been confirmed as the most important histologic parameters to be evaluated. Apical and lateral clearance of the tumor are significantly correlated with the recurrence rate. If an adequate lateral border of healthy tissue is present on the specimen, conization may be considered as definitive treatment of MIC.

Breast MRI screening in patients with increased familial and/or genetic risk for breast cancer: a preliminary experience.

AIMS AND BACKGROUND: Breast cancer is the most common cancer affecting women, and it is associated with or due to a genetic predisposition in 5%-10% of the cases. Owing to the higher risk of developing breast cancer and the early onset of the disease in women proved or suspected to be carriers of a breast cancer susceptibility gene, a dedicated screening should be offered as a less invasive approach with the otherwise suggested prophylactic mastectomy. This should be optimized in order to overcome the limitations of conventional breast imaging with the application of new technologies such as breast magnetic resonance imaging. METHODS: A diagnostic protocol for routine control in patients at high risk of developing breast cancer has been prepared. Within a 7-month period, 23 patients suspected or proved to carry a breast cancer susceptibility gene underwent breast magnetic resonance imaging. RESULTS: Four breast cancers were identified with breast magnetic resonance imaging. In these cases, mammography was negative because of the density of the parenchyma or for its fibroglandular pattern. Ultrasound was negative in 2 cases, not specific for malignancy in 1 case, and considered as only possibly malignant but with biopsy recommendation on the basis of magnetic resonance findings in the last one. Clinical analysis was positive for a mass in 2 cases. CONCLUSIONS: The accuracy of breast magnetic resonance imaging is known to be higher than that of conventional imaging in the study of breast parenchyma. High spatial resolution, no breast density influence and multiplanarity can give more detailed information about the smaller lesions and the right extension of the disease. Preliminary studies where breast magnetic resonance imaging is performed in addition to mammography within this group of patients are encouraging. We also believe that the application of breast magnetic resonance imaging can be very useful in the detection of cancer as early as possible with the aim to obtain the highest chance of survival after treatment.

Nerve-sparing radical hysterectomy: a pilot study.

Nerve-sparing radical hysterectomy has increasingly been used for cervical cancer, with less morbidity. We aimed with this study: i) to describe an alternative technique of nerve-sparing radical Piver III hysterectomy, using the CUSA, in which attention was given to the uterosacral ligament and cardinal ligament; ii) to evaluate the feasibility of this new nerve-sparing technique; iii) to describe the surgical anatomy of the autonomic nervous system; iv) to assess the early incidence of bladder dysfunction. Twelve consecutive patients with local-regional advanced cervical cancer were enrolled in the study on nerve-sparing radical hysterectomy with extended pelvic lymphadenectomy. The mean age was 44 years (range, 30-59), mean body mass index was 24 kg/m2 (range, 18-30), mean operating time was 217 mins (range, 195-240), and mean blood loss was 437 cc (range, 200-750). The average hospitalization time was 9 days (range, 5-15 days). Two patients presented pathologically positive parametrium. Two of 12 (17%) patients were discharged with self-catheterism. In the first outpatient follow-up, 1 patient had recovered spontaneous voiding. The nerve-sparing technique with CUSA can be an option to reduce radical hysterectomy-related morbidity. The technique proved to be feasible, with promising results in terms of preventing bladder dysfunction. An elevated body mass index and large tumors can impair the performance of the technique. Further studies clarifying neuroanatomy and neurophysiology of autonomic nervous structures, as well as a prospective controlled trial on nerve-sparing radical hysterectomy should be carried out to confirm our data.