Marion Kiechle

Risk of Breast and Ovarian Cancer After Prophylactic Mastectomy and Salpingo‐Oophorectomy in BRCA1 /2 Germline Variant Carriers: A Retrospective Cohort Study From a Single German Center

ABSTRACT Background As the data on BRCA1/2 ‐associated breast and ovarian cancer prevalence after prophylactic surgery has not been exhaustively investigated yet, we aimed to evaluate the cancer prevalence in a single center cohort of BRCA1 and BRCA2 carriers after conducting prophylactic mastectomy, as well as prophylactic bilateral salpingo‐oophorectomy (PBSO) respectively. Methods We included 875 women that were tested positive for a germline variant in the BRCA1/BRCA2 gene (gPV) between 2002 and 2022 at the Center of Hereditary Breast and Ovarian Cancer of the Technical University Munich Germany. Mean follow up was 7.2 years (range 0–44 years; 95% CI: 6.70 to 7.70). We differentiated breast and/or ovarian cancer diseased ( n  = 643) and non‐diseased BRCA1/2 carriers ( n  = 232). Results Our analysis confirmed the effectiveness of prophylactic surgeries in genetically predisposed women with a gPV in the BRCA1 /2 gene. We observed no breast cancer after prophylactic bilateral mastectomy, 2 contralateral breast cancer diseases after contralateral prophylactic mastectomy and 1 extraovarian serous adenocarcinoma after PBSO. Within the entire study collective, a total of 293 have undergone PBSO, with 6 women having an incidental finding of ovarian cancer and STIC respectively (=2.0%; 1.7% gBRCA1 and 0.3% gBRCA2 ). Our data suggests that, particularly regarding ipsilateral secondary cancer (ISC), higher oncological safety can be achieved through mastectomy rather than breast‐conserving surgery (BCS). In the group of patients who had a second breast cancer and were treated with BCS during their first cancer, 18.3% showed an ISC. Within the patients who were first treated with a mastectomy, only 4.3% showed an ISC. Conclusions Prophylactic surgeries demonstrate high oncological effectiveness in gPV BRCA1/2 carriers. In particular, mastectomy may provide greater protection against ISC compared with BCS. Further studies will have to be conducted to compare ipsilateral cancer prevalence after breast‐sparing surgery and mastectomy.

PARP inhibitor-induced anti-tumour chemokine response is suppressed by dipeptidyl peptidase 4 (DPP4) in ovarian cancer

Abstract Background Inhibitors of poly(ADP-ribose) polymerase (PARPi, e.g. olaparib) induce a tumour-suppressive chemokine release via STING in homologous recombination deficient (HRD) and proficient (HRP) cancers. Methods Dose-dependent effects of olaparib on HRD (ID8-Brca2 (−/−) ) and HRP (ID8) ovarian cancer cell proliferation and chemokine release. Survival of immunocompetent and immunocompromised ID8 mouse models treated with different olaparib doses. Inhibition and overexpression of the chemokine-inactivating dipeptidyl peptidase 4 (mDPP4) in HRD and HRP mouse models. Correlation of hDPP4 immunohistochemistry staining with survival in 208 high-grade serous ovarian cancer patients. Results In our study, olaparib induced the chemokines mCCL5 and mCXCL10 in a dose-dependent manner in HRD and HRP ovarian cancer cells. An optimised olaparib concentration induced chemokine release and improved survival in the syngeneic HRD ovarian cancer mouse model but not in immunocompromised mice, likely promoting synergism of immune activation and tumour cell cytotoxicity. Overexpression of mCCL5- and mCXCL10-cleaving mDPP4 induced resistance to olaparib in the HRD mouse model. Conversely, mDPP4 inhibition led to the reversal of intrinsic PARPi resistance in the HRP mouse model. Conclusions This study highlights the immune system-activating properties of PARP inhibitors and suggests harnessing these for effective PARPi therapy in ovarian cancer, especially in the context of HRP disease.

Calculating Future 10-Year Breast Cancer Risks in Risk-Adapted Surveillance: A Method Comparison and Application in Clinical Practice

Abstract The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) has successfully implemented risk-adapted breast cancer surveillance for women at high breast cancer risk in Germany. Women with a family history of breast and ovarian cancer but without pathogenic germline variants in recognized breast cancer risk genes are recommended annual breast imaging if their predicted 10-year breast cancer risk is 5% or higher, using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk model, as outlined in the current GC-HBOC guideline. However, women who initially do not meet this risk threshold may do so later, even if there is no new cancer in their family. To determine when this threshold is crossed, one could annually repeat BOADICEA calculations using an aging pedigree: the “prediction by aging pedigree” (AP) approach. Alternatively, we propose a simplified and more practical “'conditional probability” (CP) approach, which calculates future risks based on the initial BOADICEA assessment. Using data from 6,661 women registered with GC-HBOC, both methods were compared. Initially, 74% of women, ages 30 to 48 years, had a 10-year breast cancer risk below 5%, but 53% exceeded this threshold at an older age based on the AP approach. Among the women with an initial risk below the threshold, the CP approach revealed that 99% of women exceeded the 5% threshold at the same or an earlier age compared with the AP approach (88% of cases were within the same year or 1 year earlier). The CP approach has been implemented as a user-friendly web application. Prevention Relevance: The German Consortium for Hereditary Breast Cancer recommends annual breast imaging for women if their 10-year breast cancer risk is 5% or higher. Women who initially do not meet this risk threshold may do so later. We propose a simple method to determine future risks based on initial risk assessments.

The chemokine CX3CL1 promotes intraperitoneal tumour growth despite enhanced T-cell recruitment in ovarian cancer

T-cell recruiting chemokines are required for a successful immune intervention in ovarian cancer, and also for the efficacy of modern anticancer agents such as PARP inhibitors. The chemokine CX3CL1 recruits tumour-suppressive T-cells into solid tumours, but also mediates cell-cell adhesions, e.g. of tumour cells, through its membrane-bound form. So far, its role in ovarian cancer has only been rudimentarily addressed. We show that high CX3CL1 expression significantly correlates with worsened survival in human high-grade serous ovarian cancer (n=219). In preclinical ovarian cancer, CX3CL1 plays a dual role, as it enhances the adaptive anti-tumour response, but overall still promotes tumour growth, the latter as a feature of the intraperitoneal environment. Moreover, PARP inhibitors are able to increase CX3CL1 release from human ovarian cancer cells. Collectively, our study shows that CX3CL1 is a driver of intraperitoneal tumour growth in ovarian cancer, a feature that may compromise the anticancer effect of CX3CL1-inducing PARP inhibitors.