BACKGROUND:There is large variation in case-fatality rates of breast cancer in young women across the world. The objective of this study was to estimate the ten-year overall survival of women diagnosed with breast cancer before age 40 in six countries, by clinical presentation and by treatments received. METHODS:Data were supplied by seven centers in six countries, including the USA, Canada, Poland, Iceland, Iran and Thailand, totaling 36,861 women diagnosed with breast cancer before age 40, from 1977 to 2020. American patients from the SEER registry were sub-divided into (Non-Hispanic) White and Black. The following factors were compared across countries: year of diagnosis, tumor size, lymph node status, estrogen receptor (ER) status, use of chemotherapy, use of tamoxifen and use of radiotherapy. The Kaplan-Meier method was used to estimate ten-year overall survival for patients in each center. Cross-center comparisons are provided. The Cox Proportional Hazards model was used to estimate the impacts of the various factors on death for each center separately and for all centers combined, for all patients and for patients with stage I breast cancer. For these comparisons, SEER white women were considered the reference group. RESULTS:The mean age of diagnosis was 35.4 years. The percentage of patients with node-positive breast cancer ranged from 48.5% in Poland to 53.4% in Iceland. Mean tumor size ranged from 2.1 cm in Poland to 3.5 cm in Iran. The percent of patients with ER-negative breast cancer ranged from 34.0% in USA White women to 47.4% in Canada. The use of chemotherapy ranged from 65.4% in Thailand to 78.8% in Poland. Ten-year survival rates ranged from 52.5% (95%CI: 50.4%-54.7%) in Thailand to 77.9% (95%CI: 75.5%-80.3%) in Poland. A two-fold variation in case-fatality across centers persisted after adjusting for year of diagnosis, stage, tumor features and treatment. The difference in case-fatality across countries was greatest for patients with stage I breast cancer (four-fold variation). CONCLUSIONS:There is a wide disparity around the world in the long-term survival of women diagnosed with breast cancer before age 40, which cannot be accounted for by differences in screening, tumor stage at presentation or other tumor features. It is possible that differences in survival are due to inherent ethnic differences and/or differences in cancer management, but more research is required.

PURPOSE:BRCA carriers face high risks of developing both breast and ovarian/fallopian tube cancers (hereafter referred to as ovarian). Among BRCA carriers with ovarian cancer, it is not clear whether the risk of breast cancer is sufficiently high that risk-reducing mastectomy should be offered. This study aimed to assess the risk of breast cancer BRCA carriers after a diagnosis of ovarian cancer. METHODS:We included women with a pathogenic/likely pathogenic variant in BRCA1 or BRCA2, a diagnosis of ovarian cancer, and no other cancer history and no risk-reducing bilateral mastectomy. Women were followed for incident breast cancer from the date of ovarian cancer diagnosis or the date of baseline questionnaire, whichever came last. The 5-, 10-, and 15-year cumulative risks of breast cancer were compared for women with ovarian cancer and an age-matched set of control women without ovarian cancer. RESULTS:A total of 960 participants with ovarian cancer were identified (814 BRCA1 and 146 BRCA2 carriers). After a mean follow-up of 4.9 years, 41 women (4.3%) developed breast cancer, at a mean age at diagnosis of 57.5 years (range, 39-74). Actuarial cumulative breast cancer risks after ovarian cancer were 4.4%, 8.9%, and 11.5% at 5, 10, and 15 years, respectively. Only three breast cancer-related deaths occurred. Among 741 age-matched BRCA carriers without ovarian cancer, actuarial cumulative risks of breast cancer were 20.9%, 38.6%, and 47.2% at 5, 10, and 15 years, respectively. The hazard ratio for breast cancer, after an ovarian cancer diagnosis, compared with no ovarian cancer, was 0.18 ([95% CI, 0.12 to 0.27]; P < .0001). CONCLUSION:After ovarian cancer, BRCA carriers have a relatively low risk of breast cancer. Risk-reducing mastectomy should not be recommended routinely, but might be considered for long-term survivors. Magnetic resonance imaging surveillance and/or mammography is a realistic alternative.

Breast cancer etiology involves a complex interplay of various risk factors, with genetic alterations playing a significant role in susceptibility to the disease. While mutations in genes such as BRCA1 and BRCA2 are well established in elevating breast cancer risk, their potential role in predicting metastatic progression remains unclear. A recent study by Mei et al. suggested that a common germline variant in the PCSK9 gene (rs562556) may increase metastasis risk and lower survival rates in breast cancer patients. To investigate this association, we evaluated the relationship between the PCSK9 rs562556 variant genotypes and survival outcomes in two cohorts: patients with BRCA1 mutations and those with familial breast cancer lacking mutations in known susceptibility genes. Our study included 1052 BRCA1 mutation carriers, 467 familial breast cancer patients of unknown genetic etiology, and 1404 controls. Genotyping was performed using TaqMan genotyping and whole-exome sequencing. Survival analyses were conducted using Kaplan-Meier survival curves and Cox proportional hazards models. We found no significant association between PCSK9 rs562556 variant and breast cancer mortality or time to death following distant recurrence in either cohort. This finding does not support PCSK9 prognostic impact in breast cancer that may be modified by additional genetic or environmental factors.

BACKGROUND:Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. METHODS:We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. RESULTS:After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). CONCLUSIONS:Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

Microneedles (MNs) represent a rapidly evolving transdermal drug delivery method, with ongoing development effort s f ocused on overcoming challenges such as limited drug loading and pore occlusion. Herein, we report dissolvable MNs vaccine with excellent drug loading as well as other positive features that make it an ideal delivery carrier in tumor immunotherapy. This study employs a biodegradable polydopamine-based nano-delivery system to co-encapsulate both Toll-like receptor 7/8 agonist resiquimod (R848) and ovalbumin (OVA) antigens, which are subsequently incorporated into MN patches to achieve synergistic photothermal-immunotherapeutic effects. The MN vaccine targets tumor sites via transdermal administration, exhibiting significant therapeutic efficacy by enabling deep tissue drug release and maintaining prolonged therapeutic levels for at least 3 days. The MN tips are rapidly degraded under photothermal action to release R848 and OVA, can effectively polarizes the tumor-associated macrophages to M1-type macrophages and activate dendritic cells to enhance immune response in vivo , thereby, the MN vaccines have shown excellent efficacy and good safety, resulting in a sufficient and persistent anti-tumor cellular immune response with potent tumor immunotherapeutic efficacy. In brief, this study demonstrates that MN administration successfully delivers polydopamine-based nanotherapeutics to tumor sites and validates their anti-tumor efficacy. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

It has been suggested that women with a pathogenic variant (mutation) in BRCA1 or BRCA2 are at a higher risk of developing high-grade endometrial cancer. Furthermore, significantly higher follicular (but lower luteal) endometrial thickness, a surrogate marker for endometroid adenocarcinoma risk, has been reported for this high-risk population. Given that medications known to affect endometrial thickness (i.e., tamoxifen, oral contraceptives) are often indicated for BRCA mutation carriers, it is important to elucidate substantial differences exist in carriers. Thus, we conducted a retrospective chart review of endometrial thickness among women with a BRCA1 or BRCA2 who had an intact uterus and were referred to a specialized ovarian cancer clinic between 2007 and 2016. Clinical data was collected from chart review, while endometrial thickness (millimeters; mm) was abstracted from transvaginal ultrasound reports with endometrial dating and compared to published levels in the general population. In total, 114 women were identified, 73 of whom were premenopausal and 41 who were postmenopausal. Among premenopausal women, the median follicular endometrial thickness found was 7.00 mm (n = 40, range 3–13) compared to 6.8 mm (range 2.4–14) in non-carriers and the median luteal endometrial thickness was 10.85 mm (n = 30, range 5–18), compared to 9.6 mm (range 3.3–18.2) in non-carriers. Among postmenopausal women, the median menopausal endometrial thickness was 4.0 mm (n = 41, range 1–18) compared to 4.0 mm (range 1–25) in non-carrier controls. Although based on small numbers, we found no significant difference in the endometrial thickness of BRCA mutation carriers versus non-carriers.

Background: Endometriosis affects an estimated 10% of reproductive-aged women and is associated with increased ovarian cancer risk. While BRCA1/2 mutations are established risk factors for ovarian cancer, their association with endometriosis remains unclear. This study aimed to characterize the prevalence and clinical features of endometriosis within a large cohort of BRCA mutation carriers. Methods: A descriptive analysis was conducted using data from a multi-center longitudinal cohort of women with pathogenic BRCA variants. Reproductive history and related factors were collected through self-reported questionnaires and compared. Results: Among 16,950 BRCA carriers, the prevalence of endometriosis was 2.4%. Compared to BRCA carriers without endometriosis, those with endometriosis were more likely to carry a BRCA2 mutation, have post-secondary education, and experience earlier menarche. BRCA carriers with endometriosis had a lower ovarian cancer prevalence than those without (10% vs. 15%, p < 0.001). Conclusions: This is the first study of this scale to report the prevalence of endometriosis among BRCA mutation carriers, which was lower than previously reported in the general population. The association between endometriosis and ovarian cancer does not appear to be generalizable to this population. Further prospective studies are warranted to clarify this association among BRCA mutation carriers.

10506 Background: Use of menopausal hormone therapy (MHT) is contraindicated for women with a personal history of breast cancer. This topic is of importance among women with a pathogenic or likely pathogenic variant (mutation) in BRCA1 or BRCA2 given their tendency to develop early onset disease as well as the recommendation to undergo oophorectomy prior to natural menopause. Methods: We conducted a prospective analysis of MHT use following breast cancer in BRCA carriers and the risk of death. The study included BRCA carriers with a diagnosis of breast cancer, no history of another cancer, no prior MHT use, and who were enrolled in a longitudinal study. Women who initiated MHT after their diagnosis were matched to women who did not use MHT on year of birth, age of diagnosis, and treatments received – resulting in 183 matched pairs. We followed women from the date of first MHT use in the exposed and the matched date in the unexposed. Cox proportional hazards was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the risk of death associated with MHT use. Results: Among the 183 MHT users, 53 (29%) used a local MHT and 130 (71%) used a systemic MHT. After 6.0 years of follow-up (range 0.01-22.7); there were 9 (4.9%) deaths in the MHT group vs. 22 deaths (12%) in the no MHT group ( P = 0.01). The corresponding number of breast cancer deaths were 6 (3.3%) vs. 16 (8.7%) ( P = 0.03). The HR for all-cause mortality was 0.31 (95%CI 0.14-0.69; P = 0.004) and for breast cancer-specific mortality was 0.27 (95%CI 0.10-0.70; P = 0.007). The corresponding risk estimates for all-cause death by invasiveness were 0.25 (95%CI 0.11-0.61; P = 0.002) and 0.54 (95%CI 0.07-4.02; P = 0.54) for invasive disease and DCIS, respectively. All-cause mortality with use of systemic MHT was 0.27 (95%CI 0.11-0.67; P = 0.005) and was 0.19 (95%CI 0.03-1.45; P = 0.11) for local MHT. Compared to never HRT use, the HR for E-alone was 0.35 (0.12-1.02; P = 0.05) and was 0.58 (95%CI 0.08-4.29; P = 0.59) for E+P. Subgroup analyses by formulation, gene mutation and tumour pathology are on-going. Conclusions: Although based on small strata, the preliminary findings are suggestive of no increased risk of death with MHT use after BRCA -breast cancer and may offer an opportunity to improve quality of life in this unique population. Replication in larger datasets are needed.

BACKGROUND:It is not clear if breastfeeding and/or parity are associated with the risk of breast cancer among women with a germline pathogenic variant in BRCA1. We sought to evaluate the associations of these two factors with early-onset breast cancer in the BRCA1 pathogenic variant. METHODS:This case-control study included individuals with a BRCA1 pathogenic variant enroled in a longitudinal study using reproductive and disease histories ascertained at the time of enrolment. Cases had invasive breast cancer prior to age 45, and controls had no breast cancer prior to age 45. Logistic regression was used to evaluate the associations of parity and breastfeeding with cancer risk. RESULTS:Parity per se was not associated with breast cancer risk (OR = 1.09; 95%CI 0.95-1.25); however, among women who never breastfed, the OR for parous vs. nulliparous women was 1.45 (95%CI 1.20-1.75). After matching for parity, ever breastfeeding was associated with 25% lower odds of breast cancer (95%CI 0.61-0.91), and the odds ratio was 0.53 (95%CI 0.40-0.72) for those who breastfed for 20 or more months. DISCUSSION:Our findings suggest a potential role for breastfeeding in the prevention of young-onset breast cancer among individuals with a BRCA1 pathogenic variant and provide insight into possible prevention targets.

OBJECTIVE:Early surgical menopause is associated with a higher risk of mild cognitive impairment among women in the general population; this association has not been studied among women with a BRCA1 or BRCA2 mutation. This study aimed to describe the impact of clinical and host factors including bilateral oophorectomy on the probability of amnestic mild cognitive impairment among BRCA mutation carriers. METHODS:This cross-sectional study extends from a longitudinal observational study of hereditary breast and ovarian cancer that has been ongoing since 1995. The Cogniciti Brain Health Assessment was administered from 2017 to 2020 among 752 women with a BRCA mutation in Canada and the United States. The probability of amnestic mild cognitive impairment was derived from the age at test completion and 2 memory task results from the Cogniciti Brain Health Assessment, and was categorized as high or low. Self-reported details on clinical and host factors were collected from biennial research questionnaires. RESULTS:There were 21 (2.8%) women with a high probability of amnestic mild cognitive impairment and 731 (97.2%) women with a low probability. Women with a high probability were on average older at the time of cognitive assessment (63.9 vs 57.4 years, p < .001) and less likely to undergo oophorectomy for cancer prevention (55.0% vs 86.3%, p < .001) compared with women with a low probability. Among those who underwent oophorectomy for cancer prevention, women with a high probability were older at the time of surgery compared with those with a low probability (55.0 vs 46.3 years, p = .04). CONCLUSIONS:The findings suggest no short-term impact of bilateral oophorectomy on the probability of amnestic mild cognitive impairment among BRCA mutation carriers. A higher probability was predominantly attributed to older age at cognitive assessment. It is prudent to continue to monitor this population for potential long-term adverse effects following preventive surgery or cancer treatment.

BackgroundThe lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated.MethodsA total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Subjects were followed from the date of baseline questionnaire or age 40 years (whichever came last) until a new diagnosis of pancreatic cancer, death from another cause, or date of last follow-up.ResultsThirty-four incident pancreatic cancer cases were identified in the cohort. The annual risk of pancreatic cancer between age 40 and 80 years was 0.04% for BRCA1 carriers and 0.09% for BRCA2 carriers. Via the Kaplan-Meier method, the cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%-4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%-5.4%) for BRCA2 carriers. Only two of the 34 cases reported a first-degree relative with pancreatic cancer (hazard ratio, 4.75; 95% CI, 1.13-19.9; p = .03). Risk factors for pancreatic cancer included alcohol intake and a history of diabetes. The 5-year survival rate for the 34 cases was 8.8%.ConclusionsThe lifetime risk of pancreatic cancer is approximately 2% in women with a BRCA1 mutation and 3% for women with a BRCA2 mutation. The poor survival in hereditary pancreatic cancer underscores the need for novel antitumoral strategies.

OBJECTIVE:Inherited BRCA1/2 pathogenic variants (mutations) confer high lifetime risks of breast and ovarian cancers. Estimating the cumulative ovarian cancer risk following a breast cancer diagnosis in these women will help guide decisions regarding preventive salpingo-oophorectomy. METHODS:Women carrying a BRCA1 or BRCA2 mutation were followed after breast cancer and completed follow-up questionnaires every two years. The 15-year cumulative risk of ovarian cancer was estimated for women with a prior history of breast cancer and for matched control women without breast cancer. RESULTS:A total of 2084 BRCA carriers with breast cancer (1515 BRCA1, 569 BRCA2) were included. During a mean follow-up of 3.9 years, 71 ovarian/fallopian carcinomas were diagnosed (66 BRCA1, 5 BRCA2). The 15-year cumulative ovarian cancer risk was 14.9 % in BRCA1 and 5.1 % in BRCA2 carriers. Women with breast cancer were compared to those without; 1378 matched pairs were included. The 15-year cumulative risk of ovarian/fallopian cancer was 10.8 % in women with a history of breast cancer versus 25.9 % in those without. Among BRCA1 carriers, the risk was 12.2 % in women with breast cancer and 32.0 % in those without. Among BRCA2 carriers, the 15-year ovarian cancer risk was 2.0 % in both groups. CONCLUSIONS:Ovarian cancer risk remains high in BRCA1/2 carriers following breast cancer diagnosis. For BRCA1 mutation carriers, the risk is lower than in women without breast cancer. However, for both BRCA1 and BRCA2 the ovarian cancer risk is elevated, and considering the poor prognosis associated with ovarian cancer, risk-reducing salpingo-oophorectomy is strongly recommended for women with BRCA-associated breast cancer.

BACKGROUND:Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. METHODS:BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. RESULTS:A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1-15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9-24.4%) compared to other PVs (28.8%) (p = 0.02). CONCLUSIONS:Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.