Preventive Measures for Patients with an Elevated Genetic Risk for Gynecological Malignancies, in Particular Familial Breast and Ovarian Cancer

Background: Approximately 70 550 women receive a diagnosis of breast cancer in Germany each year. Ovarian cancer is much rarer, with approximately 7180 new cases per year. A woman’s individual risk of breast and ovarian cancer can be quantitatively estimated with tools that are available online; these are playing an increasingly important role in genetic counseling. Environmental factors, lifestyles, and discoveries in epigenetics all need to be taken into account. An understanding of potential preventive measures for patients at elevated genetic risk of gynecological malignancies is becoming increasingly important for precise counseling in clinical practice.

Methods: We conducted a literature search in PubMed up to September 2025, taking into account current guidelines on primary, secondary, and tertiary prevention for women at elevated genetic risk of gynecological malignancies, with a particular focus on familial breast and ovarian cancer.

Results: The lifetime risk of breast cancer in women with a pathogenic variant of the BRCA1 or BRCA2 gene is approximately 70%. For ovarian cancer, it is approximately 44% and 17%, respectively. Primary prevention includes risk-reducing surgery such as mastectomy and oophorectomy/salpingectomy, as well as the use of certain preventive drugs. An intensified early detection program for breast cancer is a secondary prevention measure. Tertiary prevention includes the option of further risk-reducing measures, such as contralateral mastectomy and the use of PARP inhibitors, for women already under treatment for hereditary breast or ovarian cancer.

Conclusion: This article highlights the wide range of preventive options available for hereditary gynecological malignancies.

Cite this as: Ditsch N, Aktas B, Banys-Paluchowski M, Speiser D, Golas MM, Fasching PA: Preventive measures for patients with an elevated genetic risk for gynecological malignancies, in particular familial breast and ovarian cancer. Dtsch Arztebl Int 2025; 122: 648–54. DOI: 10.3238/arztebl.m2025.0173

Preventive measures for lowering the risk of cancer are becoming increasingly important. One purpose of such measures is to prevent cancer from developing. Another is to detect cancer as soon as possible if the disease has already developed, to limit secondary consequences and the risk of recurrence. Genetic predisposition is an important risk factor for breast and ovarian cancer. The individual risks can be quantified with tools such as CanRisk (1, 2). Risk assessment must be based on a precise medical history as well as on the findings of genetic tests.

High-risk genes associated with breast and ovarian cancer were already identified in the 1990s, earlier than for many other types of cancer (3, 4). Reliable data were then gathered over a long period of observation, enabling the targeted development and, by now, the established use of preventive measures whose efficacy has been confirmed by national and international clinical trials. The much-publicized announcement by the movie star Angelina Jolie of her own increased genetic risk for breast and ovarian cancer has heightened awareness of prevention not only among the general public, but also among physicians, including those providing primary care.

In this review, we discuss genetic predisposition to breast and ovarian cancer, focusing on preventive measures.

Learning objectives

This article should enable readers to:

• understand and differentiate the main forms of prevention for hereditary breast and ovarian cancer,
• identify and categorize key risk‑reducing strategies, including medications, surgery, and lifestyle modifications; and
• evaluate the importance of individual risk assessment and genetic counseling in selecting appropriate preventive measures.

The significance of a genetically increased risk of breast and ovarian cancer

In 2020, 70 550 women and 740 men in Germany were diagnosed with breast cancer. Ovarian cancer is much less common, with 7180 new cases per year in Germany (5). Current evidence suggests that approximately 10% of breast cancers and 20% of ovarian cancers are attributable to hereditary factors, most of which are associated with highly penetrant pathogenic and likely pathogenic variants (pVs) in the germline, particularly in the BRCA1 and BRCA2 genes (6). The contributions of moderate- and low-penetrance pVs and of polygenic risk factors are currently subject of research and are not fully reflected in these figures (6, 7). The elevation of risk compared to the unaffected population depends on the pV in question; these genetic changes are therefore classified by penetrance into high‑penetrance, moderate‑ to high‑penetrance, moderate‑penetrance, and low‑penetrance variants. A growing body of evidence indicates that different pVs within the same gene can be associated with different levels of penetrance (8). This narrative literature review is based on publications up to September 2025 that were retrieved by a search in the PubMed database.

BRCA1 und BRCA2 were the first genes described in association with an increased risk of breast and ovarian cancer (3, 4). Their estimated respective prevalence in the general population is 0.11 and 0.12%, and 15 to 23% in high-risk families (eTable) (9, 10). Other core genes (e.g., PALB2, ATM, CHEK2, BARD1) and genetic variants of other types account for a further 4–6% of cases (10, 11). In addition, more than 200 common and low-penetrance gene loci have been described to date that account for a further 18% of breast cancer risk (12, 13, 14, 15, 16, 17, 18). Thus, about 40% of the increased familial breast cancer risk is associated with genetic changes.

eTable

Estimated lifetime risk of breast cancer and frequency of detection of pathogenic and likely pathogenic variants (pV) in data from the German Consortium for Hereditary Breast and Ovarian Cancer

Familial breast and ovarian cancer are inherited in an autosomal dominant manner (Box 1). In cells, the loss of BRCA1 or BRCA2 function causes faulty DNA repair and an increased risk of uncontrolled cell growth. Heterozygous pV carriers have a 50% chance of passing the pV on to their offspring. The average age of onset for BRCA1- or BRCA2-associated breast cancer is 40–45 (19), which is two decades earlier than for women in the general population (5). The lifetime risk of breast cancer in women with pV in BRCA1 or BRCA2 is approximately 70% (10), (72% [65; 79] for BRCA1 pV and 69% [61; 77] for BRCA2 pV [19]), with individual risk being influenced by personal and family characteristics. The lifetime risk of ovarian cancer increases with a pV in BRCA1 or BRCA2 to approximately 44% [36; 53] and 17% [11; 25] (19), respectively, compared to 1.4% in the general population (5). Limited data are available for men; according to current knowledge, the general lifetime risk of breast cancer is 0.1%, with a median age of onset of 71 years (5). The risk increases to 1% for BRCA1 pV carriers and 7% for BRCA2 pV carriers (20).

Box 1

Case illustration

A number of other genes aside from BRCA1 and BRCA2 are associated with an increased risk of breast cancer. Women with a pV in PALB2 have a lifetime risk of breast cancer (up to age 80) of 33% to 58% depending on individual circumstances, such as family history (21). PVs in the TP53 gene are associated with Li-Fraumeni syndrome (LFS), a genetic predisposition to a very broad spectrum of tumors, including breast cancer at a young age as well as malignancies in other organs (10, 22). The lifetime risk of breast cancer in women with a pV in TP53 is as high as 80–90% (22). The risk of breast cancer is lower (20–30%) with pVs in the ATM, BARD1, CHEK2, RAD51C or RAD51D genes (10). Biallelic pathogenic variants in certain breast and ovarian cancer-associated genes lead to characteristic clinical manifestations, such as Fanconi anemia or ataxia-telangiectasia (eBox 1).

eBox 1

Biallelic pathogenic variants in genes associated with hereditary breast and ovarian cancer

As for ovarian cancer, in addition to pVs in BRCA1 and BRCA2, a major role is played by pVs in BRIP1, RAD51C and RAD51D (a3–25), which increase the risk four- to sevenfold and may cumulatively account for 2% of cases. A possible association of breast and ovarian cancer with pVs in the Lynch syndrome genes (MLH1, PMS2, MSH2/EPCAM, MSH6) is not yet entirely clear. Determining the individual risk also requires consideration of the patient’s family history and personal circumstances.

The German Cancer Society checklist includes a point score that can serve as an aid to decision-making about the need for genetic counseling (26). Ideally, the family member who developed hereditary breast and ovarian cancer (HBOC)-associated cancer at the youngest age should be selected for genetic testing. The recommendations are based on the current guidelines of the German Gynaecological Oncology Group, AGO (27) and the German S3 guidelines for breast cancer (28) and ovarian cancer (29). These guidelines recommend testing in cases of therapeutic relevance or where there is evidence of a hereditary predisposition to cancer. The HBOC criteria are summarized in Box 2.

Box 2

Genetic testing for the following risk constellations (38)

The boundaries between the different types of prevention (primary, secondary, tertiary) and curative treatment can be fluid in practice and are sometimes interpreted differently in different medical disciplines (eBox 2) (30).

eBox 2

What is cancer prevention and what forms does it take?

When does a genetic risk imply the need for a preventive measure?

Genetic testing is carried out according to the provisions of the German Genetic Diagnosis Act (GenDG). It is billed in Germany in accordance with the EBM (Uniform Assessment Standard), ASV (Outpatient Specialist Care), or separate HBOC contracts (31). Genetic testing of BRCA1, BRCA2, and other risk genes in an index patient is considered to be indicated if at least one of the inclusion criteria listed in Box 2 is fulfilled. If no index patient is available for genetic testing, genetic testing can be offered to an apparently healthy person with a probability of at least 10% for the presence of a pV (32).

Preventive interventions in HBOC require individualized consideration (33, 34). The recommendations are based on gene-specific statistical values for the increased risk of breast or ovarian cancer, including fallopian tube cancer (32). These recommendations are discussed with the affected person in non-directive counseling to enable her or him to take an informed decision.

Primary preventive measures

Primary prevention of breast and ovarian cancer primarily involves risk-reducing surgery and chemoprevention. Bilateral risk-reducing mastectomy (BRRM, removal of the mammary glands) is the primary way to lower the risk of breast cancer. Bilateral risk-reducing salpingo-oophorectomy (BRRSO, removal of the fallopian tubes and ovaries) is the main way to lower the risk of ovarian cancer.

A Cochrane analysis (2018) on BRRM in healthy BRCA1 and BRCA2 pV carriers showed that it indeed lowered breast cancer incidence and breast-cancer-related mortality (35). In large meta-analyses, BRRM in women with these pVs was found to lower the risk by approximately 94% (35, 36, 37). For a 30-year-old woman with a lifetime breast cancer risk of approximately 40%, BRRM can increase her life expectancy by approximately three years. If the initial risk is around 85%, the gain in life expectancy is more than five years (38).

In a Dutch multicenter study, the probability of not dying from breast cancer by age 65 among carriers of a BRCA1 pV was 99.7% in the BRRM group, compared to 93% in the surveillance group. For BRCA2 pV carriers, the probability of not dying from breast cancer by age of 65 was 100% in the BRRM group and 98% in the surveillance group (40).

The ideal age for BRRM is unknown. Decisions on timing should be made individually, with consideration of the youngest age at which a family member developed the disease, as well as other personal contributing factors.

There are multiple surgical techniques for risk-reducing mastectomy, which can be combined with simultaneous or secondary breast reconstruction. The different techniques are considered equivalent in terms of oncological safety (39). The appropriate breast reconstruction procedure should be determined in consultation at a certified breast center. If a BRCA1 or BRCA2 pV is detected, the procedure is usually covered by health insurance in Germany. If a pV is detected in other genes, a request for cost coverage should be submitted to the insurer, as coverage is not guaranteed in every case due to insufficient evidence. As part of the joint decision-making process, self-help organizations for persons with a familial cancer risk, such as the German BRCA-Netzwerk e.V., can provide help and support with the decision for or against BRRM (e1). All persons for whom BRRM is considered should have detailed counseling and information on the procedure’s risks and long-term consequences and on the follow-up that will be needed thereafter. They should be given as much time as they need to take an informed decision.

As for the prevention of ovarian cancer, BRRSO is the only procedure that yields a survival advantage and an approximately 80% risk reduction (36). A meta-analysis showed that BRRSO markedly improves ovarian-cancer-specific survival, with a relative risk reduction of 81%, as well as overall survival, with a relative risk reduction of 71% (among women without prior breast cancer) (e2). It is recommended that BRSSO should be performed from the age of 35–40 in BRCA1 pV carriers who have completed their family planning, and from age 40 in BRCA2 pV carriers (10). Salpingectomy alone, without removal of the ovaries, can be considered in individual cases (e3). An additional hysterectomy does not offer any further oncological safety and should only be considered if the individual is also at increased risk of endometrial cancer, e.g., in Lynch syndrome. BRRSO is also offered to carriers of pVs in in RAD51C, RAD51D or BRIP1 after individual consultation (10).

Pharmacological prevention with antihormonal drugs that have been used to treat hormone receptor (HR)-positive breast cancer can markedly lower the cancer risk but has not become established in Germany because of its side effects and the resulting low adherence: in one study, only approximately 15% of patients took the medication regularly as prescribed (e4). Hardly any studies of pharmacological prevention in carriers of a pV have been performed; instead, large cohorts have been examined in which data on BRCA1 and BRCA2 pV carriers were secondarily extracted by subgroup analysis. In the NSABP-P1 study, taking 20 mg/day of tamoxifen for five years yielded a relative risk reduction of 49% for ER-positive breast cancer in particular, but there was an increased incidence of thromboembolism (e5). The cumulative incidence of thromboembolism after six years of tamoxifen was 21 per 1000, and the incidence of cataract development was 78 per 1000 (e6). The risk of developing endometrial cancer was increased as well, while the risk of ovarian cancer did not change. Similar findings were observed in the MAP.3 and IBIS-II studies (e7, e8), which showed a relative risk reduction of approximately 50% for breast cancer with the aromatase inhibitors exemestane or anastrozole, but also an increased incidence of osteoporosis. A favorable effect on the risk of developing ductal carcinoma in situ (DCIS) was also observed (e7, e8).

Oral contraceptives can lower the risk of ovarian cancer in carriers of BRCA1 and BRCA2 pV by 50–60% (e9). They can do so in the general population as well—from 1.17% to 0.67%, in absolute terms (e10). Their effect on breast cancer risk remains uncertain (e11, e12), and this is why they are not used for prevention (e9). After initial successes in basic research on the use of RANK ligands to prevent BRCA1-pV-associated breast cancer, the preventive effect of denosumab is now being studied for the first time in healthy BRCA1 pV carriers as a component of the randomized, double-blind BRCA-P trial (e13).

Women who undergo preventive surgery suffer physical and psychological stress, but most would opt for the procedure again, considering the expected lowering of the cancer risk (e14). Complications such as incisional pain or cosmetic impairment are mainly reported after reconstructive surgery. They are often treated as a secondary consideration in high-risk situations but should be discussed in detail in presurgical counseling (e14).

The decision to undergo risk-reducing surgery is especially complex for younger women who wish to have children. In Germany, specialized counseling is available for women in this situation (31).

For men, there are currently insufficient data to support any benefit of primary preventive measures, whether surgical or pharmacological. Therefore, no well-founded recommendations can be made at this time. With increasing data collection on men with pV, more precise recommendations should become possible in the future. It remains to be seen whether health insurance providers would cover the costs of such treatment.

Lifestyle changes also fall within the scope of primary prevention for genetic risk of breast or ovarian cancer (e15). The focus is on nutrition, exercise, and avoiding obesity and certain toxins (smoking) (e16, e17, e18).

Secondary preventive measures

Secondary prevention for breast cancer is achieved through an intensified surveillance program. Unlike risk-reducing measures, secondary prevention (by definition) does not prevent the disease from arising. Most of the available data on secondary prevention are derived from cohort and observational studies (27, 28). The findings suggest that, in women with a BRCA1 pV, monitoring with magnetic resonance imaging (MRI) is associated with a reduction in breast cancer mortality compared to no MRI monitoring. After a median observation period of 9.2 years, 0.8% of women in the MRI surveillance program had died of breast cancer, compared to 3.2% of the group without MRI surveillance (e19). In the intensified surveillance program for breast cancer, MRI monitoring is initiated at the earlier of the following two points in time:

• One criterion is based on the risk of disease given a confirmed pV. For example, in the case of a BRCA1 pV, this is the age of 25 years.
• The second criterion is the earliest age of breast cancer diagnosis within the respective family. Surveillance should begin five years prior to this age.

The following principles apply to the multimodal surveillance program: For high-risk patients with pVs in BRCA1, BRCA2, TP53, PALB2, or STK11 breast ultrasound is performed every six months, supplemented by an annual MRI and a mammogram every one to two years. Mammography is generally recommended from age 40 onward because of the density of the glandular tissue. Mammography should be carefully considered for carriers of a TP53 pV. A risk-adapted, intensified surveillance program has been developed for carriers of pVs in genes that are classified as moderate risk (ATM, BARD1, CDH1, CHEK2, PTEN, RAD51C, RAD51D). In this program, the frequency of ultrasound examinations is lowered to once a year. Women with a negative testing result for HBOC but with a calculated 10-year breast cancer risk of ≥ 5%, are also offered intensified surveillance as part of the HBOC program prior to their 51st birthday, as well as in follow-up care after an initial breast cancer diagnosis before age 45 (38).

To date, there is no specific surveillance program for men, so they are advised to undergo cancer screening as part of standard care and to perform targeted self-examination (e20, e21). In clinical practice, ultrasound examinations may be considered or men may be referred to the consultation service at HBOC centers.

There is currently no established surveillance program for ovarian cancer, because studies on reliable early diagnosis have not demonstrated any benefit (e22).

Tertiary preventive measures and curative treatment

Tertiary prevention refers to measures taken after the onset of disease, with the following goals:

• preventing or slowing the progression of the disease,
• avoiding complications,
• improving the patient’s quality of life (30).

Approaches include risk-reducing procedures after cancer has occurred in order to lower the risk of secondary malignancy (e23). These, too, should preferably be carried out at certified breast and gynecological oncology centers. Patients who are already affected are more likely to opt for further risk-reducing surgical procedures than persons who are not affected (e24). A nationwide analysis from the Netherlands examined overall survival after contralateral risk-reducing mastectomy (CRRM) in 583 breast cancer patients with BRCA1 or BRCA2 pV, with a median follow-up of 11.4 years. Mortality was lower in the CRRM group than in the early surveillance group (9.6 vs. 21.6 per 1000 person-years) (e25). A retrospective cohort study of 5290 patients showed benefits for BRCA1 or BRCA2 pV carriers up to the age of 40 who underwent unilateral breast cancer surgery followed by secondary mastectomy (BRRM) and/or bilateral risk-reducing salpingo-oophorectomy (BRRSO). Women who underwent risk-reducing surgery had an improved overall survival compared to those who did not, with a relative risk reduction of 35% (adjusted hazard ratio [HR] 0.65; 95% confidence interval: [0.53; 0.78]). Twenty years after the diagnosis of breast cancer, this yields an average gain in life expectancy of approximately 1.24 years (e26). Patients with BRRM and/or BRRSO also had a lower risk of developing breast or ovarian cancer again, or of dying from it. At a median follow-up interval of 8.2 years, patients with BRCA1 or BRCA2 pV and BRRM had a 42% lower risk of breast cancer recurrence or secondary malignancy. BRRSO was associated with a 42% lower relative risk of death and a 32% lower relative risk of breast cancer recurrence or a second primary malignancy. The survival benefit of BRRSO was different for BRCA1 and BRCA2 pV, with a greater reduction in the relative mortality risk in patients with pV in BRCA1 (56%) than in those with pV in BRCA2 (14%). The benefit of BRRSO also varied depending on the breast cancer subtype, with the greatest survival benefit among patients with triple-negative breast cancer (TNBC) (56% lower risk of death) and a 20% lower risk of death in those with hormone-receptor-positive breast cancer. In summary, younger patients with BRCA1 or BRCA2 pV who have already developed unilateral breast cancer and have a good prognosis for their initial disease derive the greatest benefit from BRRM and BRRSO (e26).

Just like the treatment of sporadic breast cancer, the treatment of hereditary breast cancer depends on the initial tumor stage, tumor biology, age, and prognosis of the disease (e27). Depending on breast size and tumor extent, local treatment may consist of either breast-conserving therapy or mastectomy. Mastectomy has been shown to reduce the risk of local recurrence without conferring a benefit in overall survival compared with breast-conserving therapy (e28). The axillary approach and the possible indication for radiation therapy are also the same as for sporadic breast cancer.

Larger prospective trials of radiotherapy for patients with LFS are still pending. TP53 pV in LFS impairs the apoptosis of cells with DNA damage; this might render cancer cells less responsive to radiotherapy and lead to the accumulation of further somatic mutations. Therefore, in cases of TP53 pV, it is recommended to avoid radiotherapy and, in the case of breast cancer, to opt for mastectomy (e29, e30, e31).

Taxane-based chemotherapy is recommended, as for sporadic forms. No recommendation for the obligatory additional use of platinum derivatives can be derived from the available data, but, in TNBC, the data supporting the benefit of adding platinum derivatives are robust, and this has now become standard treatment (e32).

PARP (poly[ADP-ribose] polymerase) is an enzyme involved in DNA repair that can maintain repair in BRCA1 or BRCA2 pV. Inhibition of PARP therefore promotes programmed cell death of cells with BRCA1 or BRCA2 pV (e33, e34). In the OlympiA study, the PARP inhibitor olaparib, used after the completion of neoadjuvant or adjuvant therapy, yielded a significant advantage in invasive disease-free survival (iDFS) in patients with germline pV in BRCA1 or BRCA2 and early, HER2-negative breast cancer (e35). After a median follow-up period of 3.5 years, 134 events occurred in the olaparib arm, compared to 207 in the placebo arm (e36), corresponding to 14.5% in the treatment group and 22.6% in the placebo group. At the same time, there were fewer deaths in the treatment group: 75 in the olaparib cohort, corresponding to 8.1%, versus 109 in the placebo group, corresponding to 11.9% (e36). The percentage of patients still alive four years after randomization was 89.8% in the olaparib group and 86.4% in the placebo group (a 3.4% difference, 95% confidence interval [–0.1; 6.8]).

The extended data analysis with a median follow-up of 6.1 years showed sustained efficacy of olaparib without additional toxicity signals (e37). In the overall cohort of 1836 patients, invasive disease-free survival (iDFS) after six years was 9.4% higher than in the placebo arm (e37).

 On the basis of the OlympiA study inclusion criteria, olaparib has been approved for patients with early-stage triple-negative and hormone receptor-positive HER2-negative breast cancer. All PARP inhibitors are highly effective and well tolerated and can be given orally (e38). Olaparib has also been approved for women with advanced ovarian cancer who have a pV in BRCA1 or BRCA2 and/or genomic instability (e39).

Overview

Preventive measures are becoming increasingly important for persons with a genetic predisposition to breast and/or ovarian cancer. This applies in particular to primary prevention, but also to secondary and tertiary prevention. The prerequisite for appropriate management is comprehensive information on the genetic tumor predisposition in the individual case, derived from the personal and family history and the detection of germline pVs. Despite clear recommendations, testing in Germany remains inadequate (e40). It is therefore essential to raise awareness of the need to identify and test persons at risk, in order to enable targeted prevention and more precise therapy.

Conflict of interest statement
MMG has received reimbursement of travel expenses from the German Society for Senology.

 PAF has received funding from Biontech, Pfizer, Cepheid, Novartis, Daiichi-Sankyo, AstraZeneca, Eisai, Merck, Sharp & Dohme, Lilly, SeaGen, Roche, Agendia, Gilead, Mylan, Menarini, Veracyte, and GuardantHealth.

 BA has served as a paid consultant for, and has received lecture honoraria and reimbursement of travel expenses from, AstraZeneca.

 MBP has served as a paid consultant for, and has received honoraria for presentations from, the following companies: Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Medical, Syantra, resitu, Pierre Fabre, and ExactSciences. She has received reimbursement for travel expenses and/or meeting attendance fees from Eli Lilly, ExactSciences, Pierre Fabre, Pfizer, Daiichi Sankyo, Roche, and Stemline.

 DS has received lecture honoraria from, and has served as a paid consultant for, AstraZeneca and Pfizer.

 ND is on the advisory boards of Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, and Exact Sciences. She has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Exact Sciences, Pierre Fabre, I-Med Institute, Merit Medical, pfm medical, Medi-Seminar GmbH, Roche, Lilly, Pfizer, Gilead, Novartis, and Onkowissen. She has received grants from pfm medical ag for manuscript preparation and research funding from Gilead and BZKF.

Manuscript submitted on 24 March 2025, revised version accepted on 29 September 2025.

 

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Nina Ditsch

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