Oncologic Considerations for Safe Gender-Affirming Mastectomy: Preoperative Imaging, Pathologic Evaluation, Counseling, and Long-Term Screening.

SUMMARY: There remain significant gaps in the evidence-based care of patients undergoing gender-affirming mastectomy with regard to implications for breast cancer development and screening. The current clinical evidence does not demonstrate an increased risk of breast cancer secondary to testosterone therapy in transgender patients. Gender-affirmation mastectomy techniques vary significantly with regard to the amount of residual breast tissue left behind, which has unknown implications for the incidence of postoperative breast cancer and need for screening. Subcutaneous mastectomy should aim to remove all gross breast parenchyma, although this is limited in certain techniques. Tissue specimens should also be routinely sent for pathologic analysis. Several cases of incidental breast cancer after subcutaneous mastectomy have been described. There is little evidence on the need for or types of postoperative cancer screening. Chest awareness is an important concept for patients that have undergone subcutaneous mastectomies, as clinical examination remains the most common reported method of postmastectomy malignancy detection. In patients with greater known retained breast tissue, such as those with circumareolar or pedicled techniques, consideration may be given to alternative imaging modalities, although the efficacy and cost-utility of these techniques must still be proven. Preoperative patient counseling on the risk of breast cancer after gender-affirming mastectomy in addition to the unknown implications of residual breast tissue and long-term androgen exposure is critical. Patient awareness and education play an important role in shared decision-making, as further research is needed to define standards of medical and oncologic care in this population.

Missed opportunities: Genetic counseling and testing among an ethnically diverse cohort of women with endometrial cancer.

OBJECTIVES: Lynch syndrome (LS) accounts for the majority of inherited endometrial cancers (EC), and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. The diagnosis of EC can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates in an ethnically diverse group of high-risk women. METHODS: All women diagnosed with EC between 2011 and 2016 were identified. Risk factors for LS including age, family and personal histories of Lynch-related cancers and loss of tumor mismatch repair (MMR) protein expression were identified from laboratory and medical records. Standard two-sided statistical tests were used. RESULTS: Of 583 women diagnosed with EC, 184 (31.6%) were found to have at least one high-risk characteristic for LS. Among these high-risk women, 58% were given GCR and resulting in only 35% undergoing GT. Ten of the 65 high-risk women who had GT (15.4%) were diagnosed with Lynch syndrome, and all ten met high-risk criteria. Two women of Asian race had tumors exhibiting retained MMR protein expression despite germline testing demonstrating Lynch syndrome. CONCLUSIONS: Many high-risk women do not receive GCR despite a high rate of germline mutations among these women. Improving GCR among high-risk women will lead to more subsequent GT to identify more Lynch syndrome families and prevent additional cancers. Among our ethnically diverse cohort, two women diagnosed with LS had retained MMR protein expression. GCR should be offered to women who possess high-risk characteristics despite normal MMR protein expression.

Insulin-like growth factor-I inhibition with pasireotide decreases cell proliferation and increases apoptosis in pre-malignant lesions of the breast: a phase 1 proof of principle trial.

INTRODUCTION: Estrogen inhibition is effective in preventing breast cancer in only up to 50% of women with precancerous lesions and many experience side effects that are poorly tolerated. As insulin-like growth factor I (IGF-I) underlies both estrogen and progesterone actions and has other direct effects on mammary development and carcinogenesis, we hypothesized that IGF-I inhibition might provide a novel approach for breast cancer chemoprevention. METHODS: In total, 13 women with core breast biopsies diagnostic of atypical hyperplasia (AH) were treated for 10 days with pasireotide, a somatostatin analog which uniquely inhibits IGF-I action in the mammary gland. They then had excision biopsies. 12 patients also had proliferative lesions and one a ductal carcinoma in situ (DCIS). Primary outcomes were changes in cell proliferation and apoptosis after treatment. Expression of estrogen receptor (ER), progesterone receptor (PR), and phosphorylated Insulin-like growth factor I receptor (IGF-1R), protein kinase B (AKT) and extracellular signal-regulated kinases 1/2 (ERK1/2) were also assessed. Core and excision biopsies from 14 untreated patients served as non-blinded controls. Hyperglycemia and other side effects were carefully monitored. RESULTS: Pasireotide decreased proliferation and increased apoptosis in all AH (from 3.6 ± 2.6% to 1.3 ± 1.2% and from 0.3 ± 0.2% to 1.5 ± 1.6%, respectively) and proliferative lesions (from 3.8 ± 2.5% to 1.8 ± 1.8% and from 0.3 ± 0.2% to 1.3 ± 0.6%, respectively). The DCIS responded similarly. ER and PR were not affected by pasireotide, while IGF-1R, ERK1/2 and AKT phosphorylation decreased significantly. In contrast, tissue from untreated controls showed no change in cell proliferation or phosphorylation of IGF-1R, AKT or ERK 1/2. Mild to moderate hyperglycemia associated with reduced insulin levels was found. Glucose fell into the normal range after discontinuing treatment. Pasireotide was well tolerated and did not cause symptoms of estrogen deprivation. CONCLUSIONS: IGF-I inhibition by pasireotide, acting through the IGF-1R, was associated with decreased proliferation and increased apoptosis in pre-malignant breast lesions and one DCIS. Assuming hyperglycemia can be controlled, these data suggest that inhibiting the IGF-I pathway may prove an effective alternative for breast cancer chemoprevention. TRIAL REGISTRATION: NCT01372644 Trial date: July 1, 2007.