Hereditary Prostate Cancer: From BOP to BOPP

In Version 3.2025, the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (BOP) were updated to include prostate cancer, resulting in the new “BOPP” designation. This update highlights new testing criteria for prostate cancer susceptibility genes. The guidelines now recommend that genetic testing should be considered for patients diagnosed with prostate cancer before the age of 55 years, regardless of clinical stage at presentation. Additionally, given the variable and heterogrnous clinical presentations and implications of biochemical recurrence (BCR), the guidelines clarify that testing for patients with BCR should follow the criteria established for testing at the time of prostate cancer diagnosis. Specifically, genetic testing is recommended for patients with high-risk localized, very high-risk localized, locally advanced, or de novo metastatic disease at diagnosis; those with a relevant family history of cancer; or those whose disease has progressed to overt metastatic disease.¹

Among the hereditary prostate cancer susceptibility genes, BRCA2 carries the highest relative risk of developing prostate cancer (up to a 5-fold increase, with a 20% to 60% lifetime risk) (Table 1). Although BRCA2 carriers face an increased risk of higher-grade tumors and a worse prognosis, targeted treatment with PARP inhibitors is available in the metastatic setting.² HOXB13, another gene linked to prostate cancer predisposition, is associated with up to a 3-fold increased risk of developing prostate cancer (30%–60% lifetime risk), but current evidence does not suggest an association with aggressive disease, and no precision treatment options are currently available for HOXB13 carriers. With regard to the Lynch syndrome genes, which lead to mismatch repair (MMR) deficiency, the most consistent data support an association between MSH2 and prostate cancer. Athough associations may also exist for MLH1, MSH6, and PMS2, further research is needed to confirm these relationships and define the exact magnitude of gene-specific risk. In addition, it remains unknown whether the Lynch syndrome genes are associated with aggressive disease phenotypes.³

Findings from studies such as the IMPACT trial have supported earlier and more personalized screening approaches for individuals carrying pathogenic variants in BRCA2⁴ and certain Lynch syndrome genes.⁵ Among MSH2 carriers, prostate cancer detection rates as high as 4% were observed after one round of prostate-specific antigen (PSA) screening, prompting a shift toward more refined surveillance strategies, such as age-specific PSA thresholds and incorporation of prostate MRI.⁵ Based on these findings, the PATROL trial—presented at the 2024 ASCO Genitourinary Cancers Symposium—aims to further refine prostate cancer screening protocols by incorporating factors such as age, genetic status, and PSA levels to facilitate early detection.⁶

Although pathogenic germline variants (PGVs) in Lynch syndrome genes are identified in fewer than 1% of patients with prostate cancer, the detection of a Lynch syndrome–driven tumor has significant treatment implications. Across studies such as KEYNOTE-158, durable responses to immune checkpoint inhibitors have been observed in MMR-deficient tumors,with some patients achieving long-term disease control, including those with Lynch syndrome and biallelic loss of the specific MMR gene in the tumor.⁷ “There have been a number of studies showing good responses [with pembrolizumab] for these patients, but it is important to remember that just like in BRCA1 and BRCA2, not every cancer in a genetic carrier is driven by that germline mutation,” stated Dr. Maxwell. For Lynch syndrome genes specifically, tumors with only a heterozygous PGV, without evidene of biallelic loss of the MMR gene and without a microsatellite instability–high (MSI-H) phenotype, are unlikely to respond to immune checkpoint blockade. Therefore, tumor sequencing to assess for microsatellite status and determine the presence of biallelic loss is recommended in all patients with Lynch syndrome who develop advanced prostate cancer and who are being considered for immune checkpoint inhibitor therapy.

Endometrial Cancer: Bridging the BOPP and CEG Panels

The NCCN Guidelines for Endometrial Cancer have also been updated in the latest version, and now simultaneously span across the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric (CEG). “Endometrial cancer also lives in the [gynecology] world that BRCA1 and BRCA2 are found in—which is in the BOPP panel—and Cowden syndrome—which is associated with a PTEN variant—is also in the BOPP panel. So, to comprehensively think about endometrial cancer, you still have to go in between the 2 guidelines,” stated Dr. Chen.⁸

The primary Lynch syndrome genes have well-established associations with endometrial cancer, but the level of risk is specific to each gene. Carriers of MLH1 and MSH2 face an earlier and higher risk, whereas PMS2 and MSH6 carriers often present later. The NCCN Guidelines continue to recommend universal testing for MMR deficiency using immunohistochemistry and MLH1 promoter methylation status, because it has contributed to early identification of Lynch syndrome among patients with endometrial cancer, regardless of individual risk factors. Additionally, based on data from The Cancer Genome Atlas Program, the 2023 FIGO (International Federation of Gynecology and Obstetrics) guidelines have categorized any grade POLE-mutant tumors confined to the uterus as stage IA due to their favorable prognosis. In contrast, superfically invasive p53-aberrant tumors are staged IIC due to their more aggressive behavior.⁹

The timing of risk-reducing surgery is also informed by these data. The updated NCCN Guidelines now consider hysterectomy and bilateral salpingo-oophorectomy beginning at age 40 years for individuals with MLH1 and/or MSH2 pathogenic variants. For those with MSH6, surgery can be delayed until around age 50 years. In PMS2 carriers—whose lifetime risk of Lynch-associated cancers remains relatively low—hysterectomy and bilateral salpingectomy may be considered starting at age 50 years, whereas the decision to perform oophorectomy can be more individualized. A cost-effectiveness analysis by Wright et al¹⁰ supports these risk-reducing strategies. Importantly, hormone replacement therapy should be considered for premenopausal individuals undergoing oophorectomy, provided there are no contraindications.

Hereditary Diffuse Gastric Cancer and CDH1

Diffuse gastric and lobular breast cancer syndrome is primarily caused by PGVs in the CDH1 gene. Diffuse gastric cancer is particularly difficult to detect via endoscopy because it infiltrates underneath the stomach wall. Historically, gastric cancer risk in carriers of CDH1 was estimated to be as high as 70% to 80%, but this was based on data from enriched, high-risk families. However, newer analyses suggest the penetrance is significantly lower in actual patient populations.¹¹

Recent data from clinical laboratories that included all individuals diagnosed with CDH1 PGVs estimate the lifetime risk of gastric cancer to be approximately 14% to 33% for females and 21% to 42% for males. In contrast, a cohort consisting only of individuals with advanced diffuse gastric cancer showed even lower risk estimates of approximately 7% for females and 10% for males.^8,12–14 Although noticeably higher than the general population, these lower estimates challenge the longstanding recommendation of universal prophylactic gastrectomy for CDH1 carriers. Furthermore, signet ring cell carcinoma (SRCC) lesions, which have historically been viewed as precursors to invasive cancer, are almost universal among CDH1 carriers, yet most of these lesions will not progress to invasive cancer in the absence of additional risk factors.¹² “Most people will not develop cancer,” noted Dr. Llor. “It is a changing paradigm, so the majority of these lesions are not developing into cancer as we think of it as a cause of morbidity and mortality.”

The risk of lobular breast cancer remains high in CDH1 carriers, with cumulative risk estimates ranging from 37% to 55%.^8,13,14 The spectrum of diffuse gastric and lobular breast cancer has also broadened, as families may present with gastric cancer alone, breast cancer alone, or a combination of both, reinforcing the importance of individualized genetic counseling and surveillance planning. Upper endoscopic surveillance remains limited by its inability to differentiate early SRCC lesions from cancer, and clinical decisions must be guided by updated diagnostic criteria and the involvement of multidisciplinary teams.¹⁵ Although current data are encouraging regarding close surveillance for gastric cancer using upper endoscopy, follow-up time is still quite limited, and thus long-term data are not yet available.

Testing criteria are highly variable among different guidelines, and therefore they yield a different number of identified patients after analysis.¹⁶ “We looked at 112 unselected CDH1 families through a commercial lab,” Dr. Llor explained. “Sensitivity using the International Gastric Cancer Linkage Consortium criteria was less than 19%. Yale criteria, which now has become the NCCN criteria, identified 86.6%. Current NCCN criteria for hereditary breast and ovarian cancer, on their own, already identify up to 70% of CDH1 PGV carriers, and 31% of those individuals were picked up through a set of 2 gastric cancer–focused criteria now part of the overall NCCN criteria,” he said, emphasizing the confusion caused by different guidelines.

Genetic Counseling and Access Considerations

Due to the continual updates in the NCCN Guidelines, there are increasing questions in the genetic counseling community about how to keep patients informed about changes in management over time, how to avoid confusion among family members who may receive different management recommendations based on the timing of their genetic testing, and how to engage in shared decision-making with patients, particularly in areas where data are limited and firm recommendations do not yet exist. Ms. Hampel refleted on these challenges, specifically referencing the updated NCCN Guidelines for Hereditary Diffuse Gastric Cancer, which now allow for the consideration of delaying or avoiding risk-reducing gastrectomy based on recent data showing lower lifetime gastric cancer risks than previously reported. “This is all very new, and we’re just doing the best we can with the information we have at the time,” she said. “So, shared decision-making is the best path forward, and we’ll see how we go from there.”

She also applauded recent efforts by NCCN to consolidate the management of hereditary cancer syndromes into the Genetic/Familial High-Risk Assessment Guidelines (eg, incorporating prostate cancer into BOPP and gastric cancer into CEG), rather than dispersing recommendations across disease-specific treatment guidelines. This approach helps to prevent contradictions within the guidelines and allows cancer genetics experts to weigh in on the management of these conditions. In addition, the inclusion of cancers that were previously underrepresented in hereditary cancer syndrome guidelines, such as endometrial cancer in the CEG guidelines, is a positive step forward. With these guideline updates, clinicians and genetic counselors are provided with a more streamlined framework for managing patients with a predisposition to or who have been diagnosed with hereditary cancers. Letting patients know they are receiving the best possible care is crucial, and inevitable guideline changes must be communicated to patients. At a minimum, most genetics teams encourage patients to reach out periodically to check for updates to the guidelines. Although it’s not always feasible, some providers also proactively notify patients of changes through annual follow-up visits, newsletters, educational sessions or support group meetings, or leveraging technology. Ultimately, collaborative efforts across the care team are key to improving guideline-concordant care for individuals and families affected by hereditary cancer syndromes.