Advances in precision medicine are taking place at an unprecedented rate. The National Institutes of Health (NIH) defines precision medicine as “an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person.”1 This approach will allow the development of screening, treatment, and prevention strategies for a particular disease that will optimize outcomes for individual patients. This contrasts with a more traditional one-size-fits-all approach, where disease treatment and prevention strategies are developed for the “typical” patient, with less consideration for the differences between individuals.
Genetic testing is a rapidly evolving component of precision medicine, with the potential to guide individual patient care. Multiple tumor types in different organ systems have now been identified as sharing similar genetic features, with many being inherited through the germ line. For surgical oncologists, recognizing these features may increase the likelihood of identifying familial or hereditary cancer syndromes that may affect the individual or family members screening strategies or direct treatment with specific targeted agents.
Genetic Risks for Cancer
Prostate cancer represents one model for precision medicine and illustrates how this cancer has been connected to malignancy in other organs. The study of the role of inherited germ line mutated genes in the development of prostate cancer and how these abnormal genes influence the progression to aggressive cancer is relatively new. Before 2016, the National Comprehensive Cancer Network (NCCN) Prostate Cancer Detection and Prostate Cancer guidelines did not comment on any inherited genes. For several years earlier, however, the NCCN guidelines devoted to women with hereditary breast and ovarian cancer (HBOC) syndromes noted that male relatives of women with breast cancer related mutated BRCA1/2 genes should be considered for genetic testing.2 These HBOC guidelines noted that male relatives who may harbor these inherited mutated genes were at increased risk for both prostate and male breast cancers. In late 2016, the NCCN Prostate Cancer Early Detection Guidelines first began to discuss that a family history of BRCA1/2 mutated genes should now be considered in prostate cancer screening decisions. Since 2020, the NCCN guidelines on prostate cancer treatment also recommend inherited germ line testing within men with high-risk features and metastatic disease.
The most common inherited genetic alterations associated with increased prostate cancer risk are mutations in the BRCA2 gene. Although mutations in this DNA repair pathway gene are the most common in advanced prostate cancer, dozens of other genes have been described such as BRCA1, ATM, and CHEK2, to name a few.3 This group of mutated genes was one of the first linked with increased risk for several other cancers, including breast, ovarian, and pancreatic cancer. This increased cancer risk can be found in the individual, and, if the mutated gene is inherited by other close family members, it may increase their risk for this group of solid tumors as well.
Lynch syndrome is also called hereditary nonpolyposis colorectal cancer (HNPCC). Alterations in Lynch syndrome genes that are involved in DNA mismatch repair include MLH1, MSH2, MSH6, PMS2, and EPCAM genes.4 These pathogenic DNA repair gene alterations also can be detected in other solid tumors. Lynch syndrome increases the risk of urologic cancers such as prostate cancer and upper tract urothelial carcinomas in the ureter or renal pelvis. But this increased cancer risk in Lynch syndrome goes far beyond the colon and urinary tract to include increasing the risk of endometrial, pancreatic, ovarian, stomach, and liver cancers, among others.
The NCCN guidelines for Genetic/Familial High-Risk Assessment for Colorectal Cancer 2021 noted that men with Lynch syndrome should consider their individual prostate cancer risk based on the Lynch syndrome genes and family history of prostate cancer.5 This guideline panel went on to cross reference the NCCN Prostate Cancer Early Detection Guidelines and suggested that these men undergo annual prostate cancer screening starting at age 40. In MHL1 Lynch syndrome, the lifetime risk of being diagnosed with prostate cancer was 11.6%, with only female breast cancer being higher with a 12.8% lifetime risk. Although Lynch syndrome is most often associated with GI malignancies, the impact of a diagnosis of Lynch syndrome extends beyond the general surgical oncology implications to include gynecologic and urologic surgical oncology screening and management considerations.6
Patients with a family history of pancreatic cancer may have an identified syndrome that increases risk, or they may have a familial predisposition where no specific mutation has been identified. A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. Up to 10% of all pancreatic cancers may result from inherited germ line mutations. Some mutated genes linked to familial pancreatic cancer include BRCA1, BRCA2, PALB2, CDKN2A, ATM, and the Lynch syndrome genes.7 Many of these pancreatic cancer mutated genes are strikingly similar to prostate and Lynch syndrome associated pathogenic genes. Another syndrome associated with an increased risk of pancreatic cancer includes HBOC.
Improving Identification of Genetic Risk
It is known that these mutated DNA damage response and repair genes are ineffective in protecting the integrity of normal DNA. The ensuing genomic instability caused by a cell’s inability to protect its normal DNA facilitates malignant transformation and the ongoing proliferation of invasive cancer cells. Ongoing investigations into the complex interactions with the environment or other normal and mutated genes are the likely cause of malignant transformation.
Recognizing that this group of inherited genetic alterations may increase a wide-ranging cancer risk in individuals and their families, most urologists have recently instituted changes in obtaining a family history. No longer is it sufficient to simply ask a man being screened or treated for prostate cancer about male relatives with prostate cancer. Urologists are now encouraged to ask for a more extensive family history that includes, at a minimum, identifying relatives with breast, ovarian, and pancreatic cancer, and GI or other Lynch syndrome-associated tumors. The use of more inclusive family history forms developed by commercial genetic testing labs is becoming commonplace with other online genetic assessment tools in development.8
These recent changes in urologic surgical practices in the extended family history cancer assessments ideally are being adopted in other surgical disciplines. Here is where consultation with a certified genetic counsellor can be beneficial. Genetic counsellors can review the history of the patient, the unique tumor characteristics and the family history and assist in determining what commercially available genetic panel testing should be used.9 These recommendations can be for the individual patient or, if there is need for “cascade” testing of relatives. Our genetic testing practices have moved far beyond testing individual genes to include the routine use of larger panels of genes thanks to advances in next generation sequencing (NGS).
Precision Medicine in Cancer Treatment
Building on the theme of precision medicine in identifying inherited germ line mutations, many solid tumors that share these genetic alterations also can respond to similar targeted therapeutics. There are numerous examples of newer therapies that target specific tumors with defined molecular alterations. One example is the oral PARP inhibitors. DNA repair genes (BRCA1, BRCA2, ATM, and others) make proteins that repair DNA strand breaks. With mutations in these DNA repair genes, neoplastic growth can result. Poly (ADP-ribose) polymerase (PARP) enzymes also are important in maintaining the integrity of DNA and can repair DNA single-strand breaks.
In the setting of mutated DNA repair genes, normal cellular PARP can step in and repair DNA breaks. However, if the PARP activity is blocked with a PARP inhibitor, the DNA breaks cannot be repaired, and this increases the likelihood is that a malignant cell can no longer divide, and cell death occurs.10 This unique action of PARP inhibitors in cells with these mutated DNA repair pathways has been termed “synthetic lethality”.
By identifying tumors with intrinsic defects in their DNA repair pathways – germ line BRCA1, BRCA2 or somatic mutations, for example - PARP inhibitors such as orally administered olaparib, niraparib, and rucaparib, are approved to treat a variety of solid tumors in the setting of advanced disease.11 PARP inhibitors represent another therapeutic precision medicine connection between different surgical oncology disciplines. PARP inhibitors are approved for diseases including prostate, pancreatic, peritoneal, breast, fallopian tube, and ovarian cancers.
The focus of this discussion is on the more commonly inherited genetic mutations; however, alterations identified in each disease type by comprehensive genomic profiling (CGP), or so called “somatic” tumor evaluation of the primary or metastasis, can provide insight into potential targets for treatment and future drug development.12 These tumor studies may reveal a previously detected germ line mutation or identify other mutations that may serve as therapeutic targets. Genomic profiling studies of tumors have shown that many patients with solid tumors harboring DNA repair pathway altered genes are eligible for new targeted therapies currently available, such as PARP inhibitors, immune checkpoint inhibitors, and others under investigation. A recent issue of ACS Bulletin Brief included a more extensive listing of other key mutations for targeted immunotherapy identified in gastric cancer, colorectal cancer, and cholangiocarcinoma (CCA) and their corresponding available therapies.13
More comprehensive family history and inquiry into potential genetic predisposition syndromes should now be considered a part of all surgical oncologists’ evaluation of patients with newly diagnosed solid tumors. As noted, many cases of prostate, breast, ovarian, colorectal, pancreatic, and other cancers share a surprising number of similar germ line and somatic mutations. Many resources, such as the tumor-specific NCCN guidelines, support the increasing role of genetic testing in patients and family members who could have an inherited germl ine syndrome. While these germline mutations may only be identified in a relatively small percentage of patients, finding these pathogenic genes can have a major impact in the individual and their family. Genomic profiling by somatic tumor testing is now an effective precision medicine tool to optimize patient care.
Precision medicine is significantly affecting how surgeons should approach patients with solid tumors. With increasing awareness among surgical oncologists of commonly inherited genetic alterations across multiple tumor types, patients and their families are potential benefactors in the rapidly evolving field of precision medicine through genetic testing.
