Primary Care Implications of the Expanded National Guidelines for Germline Testing of Patients Previously Diagnosed with Colorectal Cancer.

Colorectal cancer (CRC) is among the most common cancers diagnosed in the United States. Most patients are cured, have completed their routine surveillance in oncology clinics, and are being followed by primary care clinicians (PCCs). Those providers are tasked with discussing with these patients genetic testing for inherited cancer-predisposing genes that are called PGVs.Recently, the National Comprehensive Cancer Network (NCCN) Hereditary/Familial High-Risk Assessment: Colorectal Guidelines expert panel updated their recommendations for genetic testing. It is now recommended that all patients diagnosed with CRC before age 50 be tested and patients diagnosed at age 50 or older be considered for multigene panel testing (MGPT) for inherited cancer-predisposing PGVs.Here, I discuss the basis for the NCCN expanded genetic testing recommendations and highlight the salient controversies related to genetic testing. I also review the literature that suggests that PCCs identified more training as the measure needed before they are comfortable having complex discussions related to genetic testing with their patients.

Rapid Progression of Metastatic Pancreatic Adenocarcinoma During Platinum-Based Therapy in a Patient Harboring a Pathogenic BRCA2 Germline Variant.

Familial pancreatic adenocarcinoma (PDAC) is most commonly related to inheritance of a pathogenic BRCA variant (J Med Genet 2005;42:711-719). The National Comprehensive Cancer Network recommends germline testing for patients diagnosed with PDAC and recommends platinum-based chemotherapy as the preferred initial systemic therapy for patients harboring a pathogenic BRCA germline variant with PDAC (https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455). PDACs related to pathogenic BRCA germline variants typically demonstrate BRCA loss of heterozygosity (LOH), which results in ineffective DNA damage repair due to a lack of normal BRCA gene product activity. By causing DNA damage, platinum-based therapies have been shown to be highly effective therapies (Cancer Cell 2010;18:499-509, Gen Med 2015;17:569). In contrast, platinum-based therapies would be predicted to be significantly less effective for PDACs in patients with pathogenic BRCA germline variants who have cancers that lack BRCA LOH. Poly (ADP-ribose) polymerase 1 (PARP) is also key to effective DNA repair. The Food and Drug Administration has approved PARP inhibitors for patients carrying germline pathogenic BRCA variants and metastatic breast cancer or ovarian cancer (Ann Oncol 2019;30:558-566, J Clin Oncol 2015;33:244-250). PARP inhibitors would again be expected to be far less effective in patients who carry pathogenic BRCA germline variants with breast and ovarian cancers (those that lack BRCA LOH) than in those with BRCA-related breast and ovarian cancers (which typically demonstrate BRCA LOH), because PARP is involved in DNA repair. Here, we present a patient harboring a pathogenic BRCA germline variant whose PDAC grew rapidly during platinum-based therapy and lacked BRCA LOH and therefore was not likely BRCA related. Given the molecular fingerprint of BRCA-related PDAC in patients with pathogenic BRCA germline variants and the mechanism of action of platinum-based therapies and PARP inhibitors, this case underscores the importance of future studies aimed at determining whether the lack of BRCA LOH in PDACs in pathogenic BRCA germline variant carriers is a biomarker of less responsiveness to platinum-based chemotherapy and PARP inhibitors. KEY POINTS: Platinum-based therapy or Poly (ADP-ribose) polymerase 1 (PARP) inhibitor therapies are highly effective systemic therapy options for most patients with pancreatic adenocarcinoma who carry a germline pathogenic BRCA variant. In the case presented here, a patient carrying a germline pathogenic BRCA variant saw rapid progression of his pancreatic adenocarcinoma while on platinum-based therapy. Next-generation sequencing confirmed that his pancreatic cancer was likely not related to BRCA loss of heterozygosity (LOH). Studies are needed to determine, in patients who harbor germline pathogenic BRCA variants, whether similar cancers (i.e., those that lack BRCA LOH) are less responsive to platinum-based or PARP inhibitor therapies than are those more common BRCA-related cancers (i.e., those that demonstrate LOH).

Rationale for evaluating breast cancers of Lynch syndrome patients for mismatch repair gene expression.

BACKGROUND: Lynch Syndrome (LS) patients harbor germline mutations in one of several mismatch repair (MMR) genes and are predisposed to the development of colon and endometrial cancers and multiple other cancers types as well. Tumors related to LS are characterized by deficient protein expression of one or more MMR genes (dMMR) and/or demonstrate high microsatellite instability (MSI-H) (Win et al. in Breast Cancer Res 15(2):R27, 2013). The National Comprehensive Cancer Network (NCCN) Guideline states that there have been "suggestions" of increased risk of breast cancer in diagnosed LS patients, but does not endorse "increased screening above-average-risk breast cancer screening recommendations" for patients with LS (Provenzale et al. in J Natl Compr Cancer Netw 14(8):1010-1030, 2019). RESULTS: This report describes a molecularly diagnosed LS patient who developed a dMMR breast cancer. CONCLUSIONS: Sporadic dMMR breast cancers are extremely rare (Davies et al. in Cancer Res 77:4755-4762, 2017). It seems reasonable to conclude that identifying a dMMR breast cancer in a patient with known LS strongly suggests that her LS is breast cancer-predisposing. LS patients with dMMR breast cancers might therefore be considered for above-average breast cancer screening for the development of additional breast cancers. Also, the FDA recently granted approval of checkpoint inhibitor therapy for all metastatic dMMR solid malignancies (Lemery et al. in N Engl J Med 377:1409-1412, 2017). MMR expression assays in metastatic breast cancers of LS patients would represent a more focused approach to identifying patients with breast cancers who are potentially eligible for checkpoint inhibitor therapy than would be universal MMR testing of all metastatic breast cancers.

Quantitative mRNA Expression Assays and Synchronous Breast Cancers: A Case Report.

Quantitative mRNA analysis of breast tumors represents a routinely applied example of precision oncology. Currently the National Comprehensive Cancer Network (NCCN) recommends quantitative mRNA profiling (e.g., 21-gene RT PCR or Oncotype Dx assay) for nearly all surgically resected lymph node (LN) negative hormone receptor (HR) positive, HER2 negative breast cancers in order to predict recurrence risk with endocrine therapy compared to chemotherapy followed by endocrine therapy after surgery. The incidence of synchronous breast cancers is low and evidence concerning distant recurrence risk is limited, but the risk of distant recurrence from one or the other of two primary breast cancers appears to be higher than the recurrence risk of the single largest of the two cancers. In this report, a woman with synchronous primary breast cancers is described. Oncotype Dx testing was done on each of her two cancers. By assuming that the recurrence risk from each with adjuvant endocrine therapy is an independent event, the recurrence likelihood from one or the other or both is calculated. I propose that this calculated value more accurately should predict the recurrence from one or the other or both tumors with endocrine therapy or chemotherapy followed by endocrine therapy compared with using only the higher of the two Oncotype Dx estimated risks.

Should adjuvant chemotherapy be recommended to a 75-year-old woman with deficient mismatch repair (dMMR) gene product expression seen in a stage II colon adenocarcinoma with lymphovascular invasion?

The risk of recurrence from stage II colon cancer and benefit from adjuvant chemotherapy is influenced significantly by the molecular marker termed microsatellite instability and/or mismatch repair (MMR) gene product expression.1 Study results and the National Comprehensive Cancer Network Colon Cancer Guideline panel suggest that adjuvant chemotherapy (fluoropyrimidine [5-FU] +/- oxaliplatin) be considered for patients with stage II colon adenocarcinoma harboring one or more "high-risk" features.2 However, for patients with deficient-MMR (dMMR) stage II colon cancer, evidence suggests there may be a detrimental effect with adjuvant 5-FU alone.3 Finally, the addition of oxaliplatin to 5-FU does not appear to benefit older patients with stage II colon cancer.4,5 For the patient described, the challenge involved how to advise an older patient with a dMMR stage II colon cancer and a high-risk feature. The identified lymphovascular invasion in the tumor implies that adjuvant chemotherapy with either 5-FU or capecitabine +/- oxaliplatin would be reasonable considerations. However, the dMMR status of the tumor suggests that 5-FU alone would be contraindicated, and her age suggests that a lack of benefit would be expected from oxaliplatin.

Biological therapy update in colorectal cancer.

Colon and rectal cancer remain the second most common cause of cancer death in the US. Advances in the past 10 years have resulted in improved outcomes for patients. In addition to newer chemotherapeutics agents, the so-called 'targeted' or 'biological' therapies have improved survival in patients with metastatic disease. This review aims to summarize the mechanistic basis for the usefulness of these agents, the key clinical trials demonstrating their efficacy, and the studies now initiated with the hope of further incorporating their use in treating colon and rectal cancer.