Major medical societies recommend that physicians consider ordering germline testing in patients with a current diagnosis of cancer or with a personal history of cancer. Testing should be ordered as part of any initial workup, or performed on those cancers that are not responding to chemotherapy, or to guide prophylactic treatment strategies.
Germline variants are associated with an increased risk a of a variety of cancers. The most common variants are among the Lynch syndrome (MLH1, MSH2, MSH6, PMS2, or EPCAM) and BRCA1/2 genes, affecting approximately 1 in 279 and 1 in 400 Americans, respectively. Germline variants are also linked with increased morbidity and faster disease progression.
BRCA variants have been found to account for more than 30% of variants in germline-associated prostate cancer, while multiple variants with known therapeutic implications (CHEK2, ATM, PALB2, MUTYH) are also present. Since genetic risk factors that predispose patients to more aggressive diseases and lower survival rates have been identified, physicians could use this information to increase targeted screening of higher-risk individuals, stop overtreatment of lower-risk patients and guide treatment decisions.
A recent study shows that almost 5 percent of lung cancer is associated with germline variants that influenced the patients’ susceptibility. Within the study sample, the most common pathogenic variant was BRCA2, which was found in almost 50 percent of variant carriers. BRCA2 was followed in prevalence by CHEK2 (21%) and ATM (14%, though other studies have shown upwards of 50%). Likely pathogenic variants were also prevalent, including BRIP1, PALB2, and RAD50.
The risk of hereditary endometrial cancer increases almost 2-fold with the presence of a pathogenic variant in a mismatch repair gene, like ATM, PALB2, RAD51C, MUTYH, and NBN. More than 1 in 5 ovarian carcinomas are associated with germline variants. Some are attributed to genes, such as PALB2, RAD51C, TP53, and MSH6, while most, about 15%, are associated with BRCA1/2 variations.
A multisite study conducted by Mayo Clinic physicians found that 1 in 6 patients with colorectal cancer (15.5%) had a germline predisposition for the disease. CDH1 germline variations are primarily associated with Hereditary Diffuse Gastric Cancer. CDH1 codes for the E-cadherin protein, a trans-membrane glycoprotein responsible for adhesion and maintaining epithelial polarity. Its dysfunction is associated with tumor metastasis, because of the increased cell motility.
An estimated 20% of patients with triple-negative breast cancer are BRCA variant carriers, and 70% of breast cancers that develop in BRCA1 variant carriers are triple-negative.
Genetic testing prior to beginning therapy is necessary to match the treatment up with the patients and cancers likely to benefit from them. Studies confirm patients with germline cancers often behave and respond to treatment differently than somatic or sporadic cancers. For example, treatment with PARP inhibitors exploits germline mutations in BRCA1/2 and BRCA-related genes to drive synthetic lethality as an anti-cancer mechanism. This could potentially affect the treatment outcomes of many patients, including those with breast, ovarian, prostate, colorectal, pancreatic, melanoma and many more cancer diagnoses. In addition to guiding optimal surgical and therapeutic decisions, germline testing identifies patients, like those with Lynch Syndrome, for whom there may be contraindications to certain treatments.
Response to radiotherapy, platinum-based chemotherapy, androgen-deprivation therapy and use of PARP inhibitors are all life-saving considerations for prostate cancer patients, only possible after the completion of a hereditary cancer test.
Due to the high prevalence of BRCA2 in lung cancer patients, PARP inhibitors may be applied for this specific population in addition to traditional chemoradiotherapy, targeted therapy or immunotherapy, and relevant clinical trials have also shown positive results.
HR-deficient tumors due to deleterious variants in genes other than BRCA1 and BRCA2 may be sensitive to PARPi. RAD51C-deficient cancer cells were highly sensitive to Olaparib, significantly inhibiting tumor growth. Cells deficient in RAD51D were sensitive to Olaparib in a magnitude similar to the observed by silencing BRCA2. Ovarian cancer patients with germline variants tend to respond to treatment differently than patients without a known pathogenic variant, including being more sensitive to intraperitoneal chemotherapy and platinum therapy.
Triple-negative Breast Cancer patients with BRCA variations are excellent candidates for PARP inhibitor therapy, platinum derivatives and have a better response to carboplatin therapy.
Therapeutic mastectomy with contralateral prophylactic mastectomy and/or bilateral salpingo-oophorectomy are recommended for women with pathogenic variants in certain cancer predisposition genes, including BRCA1, BRCA2, PALB2, PTEN and TP53. The benefits of prophylactic mastectomy and oophorectomy are well-established within breast cancer treatment, with a 95% reduction in the risk of breast cancer after mastectomy and a 50% reduction in breast cancer risk after oophorectomy if performed under the age of 40.
Patients whose germline genetic variants match one of the treatments in a clinical trial may receive that treatment if they meet the other eligibility criteria. The trials seek to determine whether treating cancer based on these specific genetic changes is effective and improves overall survival.
Testing could indicate if patients are at an increased risk for additional, new primary cancers at the same or different locations. This allows the patient to pursue enhanced screening or preventative, prophylactic surgeries to manage their risks.
For many hereditary cancers, familial knowledge and awareness of a pathogenic variant prior to the onset of cancer can inform screening, result in earlier detection of cancer at more treatable stages, and allow prevention options such as prophylactic surgery. For those with cancer, germline testing informs choices for care and treatment.
TP53, PTEN, and STK11 variants all have recommendations for increased preventative screening, including more frequent examinations, colonoscopies and endoscopies.
TP53, PTEN, PALB2, and STK11 variants all have recommendations for increased preventative screening, including more frequent examinations, mammograms, and MRIs.
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