Noah D. Kauff

Background: Germline genetic testing is recommended for patients with pancreatic ductal adenocarcinoma (PDAC) and pre-diagnostic testing is offered to patients with a significant family history. However, only 41% of patients in our institution obtained genetic testing. We identified associations between patient social profiles and delays in obtaining germline genetic testing from New York’s largest healthcare system. Methods: Patients with PDAC were identified using our EMR between Mar 2016 and Feb 2022 with an IRB-approved protocol. Median income was extrapolated using zip code. Date of diagnosis (DOD) was recorded as the date of biopsy. Delays of testing was calculated as the difference between DOD and the date of germline test. Social work needs and insurance were captured by EMR review of social work notes. Results: 329 patients with PDAC were identified, with 135 (41%) having reports found. Availability of germline testing did not vary by median income. Pearson analysis between income and delays showed a negative correlation (r=-0.258, p=0.0025). Patients who received social security and were unemployed/disabled had significant delays (167d) in testing compared to patients receiving social security (13d) and retired or patients receiving salaries (30d). African Americans and Hispanics, classified as underserved minority, had significant delays in testing (66d) compared to not underserved patients (22.5d, p=0.021). In addition, African American patients had significant delays in testing (66d) compared to White patients (20d, p=0.0076). Patients with social work needs had significant delays in testing (104d) compared to patients without SW needs (20.5d, p=0.0002). Of the twelve patients who required SW, six required home care, three required transportation, and two required financial assistance. In addition, patients with Medicare and supplementary insurances had significant decreases in delays (10d) of germline testing compared with patients with Medicare alone (32d, p=0.0077), Medicaid (57d, p=0.020), or commercial insurances (21d, p=0.021). We identified 12 patients who had germline mutation reports before PDAC diagnosis. For patients with pre-diagnostic testing, 5 had Medicare with supplementary insurances. For the rest of patients with germline testing after the diagnosis of PDAC, 10 had supplementary insurances (p=0.0043). Conclusion: The analysis of our 329-patient cohort showed a striking and concerning negative correlation between patient income and delays in germline testing. Under-represented minority patients had significant delays in germline testing and did not obtain any pre-diagnostic testing. Social work needs and insurance may be barriers as well. Interprofessional collaborations may be required to prompt germline testing.

Background: The objectives of this study were (i) to explore whether differences in cell proliferation may help explain why most high-grade serous ovarian cancers (HGSOC) arise in the fallopian tube fimbriae (FTF) rather than in ovarian cortical inclusion cysts (CIC); (ii) to compare premenopausal and postmenopausal FTF proliferation as a reason why the age incidence of HGSOC increases at a slower rate after menopause; and (iii) to compare FTF proliferation in cycling women and women using the levonorgestrel intrauterine contraceptive system (Lng-IUS) to see whether proliferation on the Lng-IUS was lower. Methods: We studied 60 women undergoing a salpingo-oophorectomy. We used Ki67, paired-box gene 8 (PAX8, Müllerian marker), and calretinin (mesothelial marker) to study FTF and CIC proliferation. Results: FTF Ki67%+ was greater in the follicular than in the luteal phase (4.9% vs. 1.5%; P = 0.003); postmenopausal Ki67%+ was 1.7%. Ki67%+ in PAX8 negative (PAX8−) CICs was extremely low. Proliferation in PAX8+ CICs did not vary by menstrual phase or menopausal status. Follicular Ki67%+ was 2.6-fold higher in FTF than PAX8+ CICs. FTF Ki67%+ from 10 women using the Lng-IUS was not lower than in cycling women. Conclusions: Overall FTF Ki67%+ is greater than overall CIC Ki67%+. Overall FTF Ki67%+ in postmenopausal women is lower than in premenopausal women. The Lng-IUS is not associated with lower FTF Ki67%+. Impact: Ki67%+ provides an explanation of the preponderance of FTF-derived HGSOCs, and of the slower increase of HGSOCs after menopause. The Lng-IUS may not be associated with a protective effect against HGSOCs.

In Reply We appreciate the interest Dr Narod has shown in our recent report examining the incidence of uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with mutations in BRCA1 and BRCA2. While he expresses concern that the multicenter collaboration to address this specific question was initiated in 2014, he is mistaken in his interpretation that the data were not prospectively ascertained or that the initial design of the cooperating studies did not include plans for assessment of our primary end points. As was outlined in the Methods, the analysis was performed by pooling data from 3 ongoing prospective cohort studies—2 single-institution studies conducted at Memorial Sloan Kettering Cancer Center and the Abramson Cancer Center at University of Pennsylvania and 1 multicenter study, the Prevention and Observation of Surgical Endpoints (PROSE Consortium) study.^1- 3 While there are some differences in the design of the individual studies, a primary end point of all 3 studies has been to evaluate the impact of various risk reduction strategies on cancer incidence in individuals with BRCA mutations. Furthermore, to both harmonize the analytic approach across the 3 cohorts and include only strictly prospective data in the analysis, participant follow-up was included only after the latest of study ascertainment, receipt of BRCA testing results, or risk-reducing salpingo-oophorectomy.

Characteristic histopathologic features have been described in high-grade serous carcinoma associated with BRCA abnormalities (HGSC-BRCA), which are known to have relatively favorable clinical outcomes. The aim of this study was to evaluate the clinical significance of invasion patterns in metastatic HGSC-BRCA cases. Of the 37 cases of advanced-stage HGSC with known BRCA1 or BRCA2 germline mutation retrieved from our institutional files, 23 patients had a germline mutation of BRCA1 and 14 had a BRCA2 mutation. The pattern of invasion at metastatic sites was recorded and classified as a pushing pattern (either predominantly or exclusively), an exclusively micropapillary infiltrative pattern, or an infiltrative pattern composed of papillae, micropapillae, glands, and nests (mixed infiltrative pattern). Histologic evaluation of metastases was performed without knowledge of genotype or clinical outcome. Clinical data were abstracted from medical records. Median age was 56 years (range, 31 to 73 y). All patients presented at stage IIIC or IV and underwent complete surgical staging followed by chemotherapy. All 37 HGSC-BRCA cases showed either pushing pattern metastases (30; 81%) or infiltrative micropapillary metastases (7; 19%). No HGSC-BRCA case exhibited metastases composed solely of mixed infiltrative patterns. Among the 7 infiltrative micropapillary cases, 6 had a BRCA1 germline mutation versus 1 with a BRCA2 mutation. The median time of follow-up was 26 months (range, 13 to 49 mo). All 7 patients with infiltrative micropapillary metastases either experienced recurrence or died of disease (5 recurrences and 2 deaths), which was significantly worse than what was seen in patients with predominantly pushing pattern metastases, of whom 16 of 30 (53%) experienced recurrence (n=14) or died of disease (n=2) (P=0.03). In conclusion, the recognition of different invasion patterns of metastatic extrauterine HGSC-BRCA has prognostic implications. The infiltrative micropapillary pattern is associated with poor outcomes and is more frequently seen in BRCA1-associated HGSC than in BRCA2 cases.

Heemskerk-Gerritsen et al. ( 1 ) questioned the protective effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer (BC) risk in women who carry a BRCA1 or BRCA2 ( BRCA1/2 ) mutation, as previously reported. They proposed that studies addressing this question should ensure: 1) women are eligible only if they do not have breast or ovarian cancer and have both ovaries and breasts intact before DNA testing; 2) each woman is followed from the age of DNA testing; and 3) the time at risk considers RRSO as a time-dependent variable that takes value 0 before RRSO and 1 after. Using this design, their analysis of Hereditary Breast and Ovarian Cancer in the Netherlands (HEBON) data reported a BC hazard ratio (HR) by RRSO of 1.09 (95% confidence interval [CI] = 0.67 to 1.77). They hypothesized that the previously reported protective effect of RRSO on BC was because of failure to conform to one of these three design features.