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Abstract Background Triple‐negative breast cancer (TNBC) is the neoplasia most associated with BRCA1 germline pathogenic variants (PV) and is more likely to develop metastases than the other breast cancer (BC) subtypes, mainly in the lungs and the central nervous system (CNS). Recently, BRCA2 carriers were shown to have a higher risk for developing CNS metastases. However, the patterns of recurrence and metastases of BRCA2 carriers with TNBC are unknown. Methods TNBC patient data attending the A.C. Camargo Cancer Center, from 1998 through 2020, were verified either by medical records or by BRCA1/2 genetic testing carried out. Multivariable logistic regression models were fit to the data to assess the independent factors for bone and CNS metastases. Adjustment was done using all independent variables with p

To assess the role of germline pathogenic variants (PVs) in SMARCA4 and further established ovarian cancer (OC) predisposition genes in early onset OC, we investigated a clinical cohort of 206 unrelated OC index patients with an age at diagnosis of OC ≤40 years using an extended panel of 24 (candidate) cancer predisposition genes. PVs in established OC predisposition genes were most frequent in patients with high grade serous OC (21/62, 33.9%), comparatively rare in patients with epithelial OC other than high grade serous (5/74, 6.8%) or borderline ovarian tumours (2/39, 5.1%) and absent in mucinous OC (0/27). We demonstrate that germline PVs in SMARCA4 unlikely predispose for early onset OC other than SCCOHT.

Background: Triple‐negative breast cancer (TNBC) is the neoplasia most associated with BRCA1 germline pathogenic variants (PV) and is more likely to develop metastases than the other breast cancer (BC) subtypes, mainly in the lungs and the central nervous system (CNS). Recently, BRCA2 carriers were shown to have a higher risk for developing CNS metastases. However, the patterns of recurrence and metastases of BRCA2 carriers with TNBC are unknown. Methods: TNBC patient data attending the A.C. Camargo Cancer Center, from 1998 through 2020, were verified either by medical records or by BRCA1/2 genetic testing carried out. Multivariable logistic regression models were fit to the data to assess the independent factors for bone and CNS metastases. Adjustment was done using all independent variables with p < 0.2 in the univariable Cox model to describe the relationship between the independent variables until time of death. Results: A total of 388 TNBC patients were evaluated. We identified PV in BRCA1/2 genes in 21% (82/388), being 17.7% (69/388) in BRCA1 and only 3.3% (13/388) in BRCA2. A total of 120 patients (31%) developed distant metastases. Bone or CNS metastases were observed in 40% and 60% of BRCA2 PV carriers (p = 0.155), respectively. The BRCA2 carriers tended to have a higher likelihood of developing bone metastases (OR, 4.06; 95% CI, 0.82–20.01; p = 0.085), when compared to BRCA1 carriers (OR, 0.6; 95% CI, 0.12–2.87; p = 0.528). BRCA2 carriers had an OR of 1.75 (95% CI, 0.33–9.14; p = 0.503) for CNS metastasis development, while BRCA1 carriers had an OR of 0.72 (95% CI, 0.23–2.23; p = 0.574). Conclusions: Patients with TNBC and PV in the BRCA2 gene had higher frequencies of secondary bone involvement and CNS in the course of the disease. However, the BRCA2 PV did not represent an independent outcome predictor of metastases and overall survival. Efforts to increase the number of BRCA2 carriers among TNBC patients are crucial for determining their risk of developing bone and CNS metastases compared to BRCA2 noncarriers. [ABSTRACT FROM AUTHOR]

To assess the role of germline pathogenic variants (PVs) in SMARCA4 and further established ovarian cancer (OC) predisposition genes in early onset OC, we investigated a clinical cohort of 206 unrelated OC index patients with an age at diagnosis of OC ≤40 years using an extended panel of 24 (candidate) cancer predisposition genes. PVs in established OC predisposition genes were most frequent in patients with high grade serous OC (21/62, 33.9%), comparatively rare in patients with epithelial OC other than high grade serous (5/74, 6.8%) or borderline ovarian tumours (2/39, 5.1%) and absent in mucinous OC (0/27). We demonstrate that germline PVs in SMARCA4 unlikely predispose for early onset OC other than SCCOHT. [ABSTRACT FROM AUTHOR]

Abstract Nearly 80% of advanced cancer patients are afflicted with cachexia, a debilitating syndrome characterized by extensive loss of muscle mass and function. Cachectic cancer patients have a reduced tolerance to antineoplastic therapies and often succumb to premature death from the wasting of respiratory and cardiac muscles. Since there are no available treatments for cachexia, it is imperative to understand the mechanisms that drive cachexia in order to devise effective strategies to treat it. Although 25% of metastatic breast cancer patients develop symptoms of muscle wasting, mechanistic studies of breast cancer cachexia have been hampered by a lack of experimental models. Using tumor cells deficient for BARD1, a subunit of the BRCA1/BARD1 tumor suppressor complex, we have developed a new orthotopic model of triple‐negative breast cancer that spontaneously metastasizes to the lung and leads to systemic muscle deterioration. We show that expression of the metal‐ion transporter, Zip14, is markedly upregulated in cachectic muscles from these mice and is associated with elevated intramuscular zinc and iron levels. Aberrant Zip14 expression and altered metal‐ion homeostasis could therefore represent an underlying mechanism of cachexia development in human patients with triple‐negative breast cancer. Our study provides a unique model for studying breast cancer cachexia and identifies a potential therapeutic target for its treatment.

Abstract Ovarian cancer is the leading cause of gynecologic cancer death in the world, and its prevention and early diagnosis remain the key to its treatment, especially for high‐grade serous carcinoma (HGSC). Accumulating epidemiological and molecular evidence has shown that HGSC originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. Comprehensive molecular analyses and mouse studies have uncovered the key driver events for serous carcinogenesis, providing novel molecular targets. Risk‐reducing bilateral salpingo‐oophorectomy (RRSO) has been proposed to reduce the subsequent occurrence of serous carcinoma in high‐risk patients with BRCA mutations. However, there is no management strategy for isolated precursors detected at RRSO, and the role of subsequent surgery or chemotherapy in preventing serous carcinoma remains unclear. Surgical menopause due to RRSO provides a variety of problems related to patients’ quality of life, and the risks and benefits of hormone replacement are under investigation, especially for women without a previous history of breast cancer. An additional surgical option, salpingectomy with delayed oophorectomy, has been proposed to prevent surgical menopause. The number of opportunistic salpingectomies at the time of surgery for benign disease to prevent the future occurrence of HGSC has increased worldwide. Thus, the changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and therapeutic approaches.

Nearly 80% of advanced cancer patients are afflicted with cachexia, a debilitating syndrome characterized by extensive loss of muscle mass and function. Cachectic cancer patients have a reduced tolerance to antineoplastic therapies and often succumb to premature death from the wasting of respiratory and cardiac muscles. Since there are no available treatments for cachexia, it is imperative to understand the mechanisms that drive cachexia in order to devise effective strategies to treat it. Although 25% of metastatic breast cancer patients develop symptoms of muscle wasting, mechanistic studies of breast cancer cachexia have been hampered by a lack of experimental models. Using tumor cells deficient for BARD1, a subunit of the BRCA1/BARD1 tumor suppressor complex, we have developed a new orthotopic model of triple‐negative breast cancer that spontaneously metastasizes to the lung and leads to systemic muscle deterioration. We show that expression of the metal‐ion transporter, Zip14, is markedly upregulated in cachectic muscles from these mice and is associated with elevated intramuscular zinc and iron levels. Aberrant Zip14 expression and altered metal‐ion homeostasis could therefore represent an underlying mechanism of cachexia development in human patients with triple‐negative breast cancer. Our study provides a unique model for studying breast cancer cachexia and identifies a potential therapeutic target for its treatment. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the leading cause of gynecologic cancer death in the world, and its prevention and early diagnosis remain the key to its treatment, especially for high‐grade serous carcinoma (HGSC). Accumulating epidemiological and molecular evidence has shown that HGSC originates from fallopian tube secretory cells through serous tubal intraepithelial carcinoma. Comprehensive molecular analyses and mouse studies have uncovered the key driver events for serous carcinogenesis, providing novel molecular targets. Risk‐reducing bilateral salpingo‐oophorectomy (RRSO) has been proposed to reduce the subsequent occurrence of serous carcinoma in high‐risk patients with BRCA mutations. However, there is no management strategy for isolated precursors detected at RRSO, and the role of subsequent surgery or chemotherapy in preventing serous carcinoma remains unclear. Surgical menopause due to RRSO provides a variety of problems related to patients' quality of life, and the risks and benefits of hormone replacement are under investigation, especially for women without a previous history of breast cancer. An additional surgical option, salpingectomy with delayed oophorectomy, has been proposed to prevent surgical menopause. The number of opportunistic salpingectomies at the time of surgery for benign disease to prevent the future occurrence of HGSC has increased worldwide. Thus, the changing concept of the origin of serous carcinoma has provided us a great opportunity to develop novel diagnostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]