Is It Time to Expand Our Definition of "Clinical Utility"?

Currently, genetic tests that predict cancer risk or risk of recurrence in patients who have had their cancer treated with curative intent must have proven "clinical utility" to be recommended by the organizations responsible for publishing the standard-of-care guidelines for cancer care.Based on the current definition of clinical utility, most patients are denied testing for cancer-predisposing genes or pathogenic germline variants even though germline testing has been proven as highly accurate in identifying pathogenic germline variant carriers, there are measures recommended to prevent and diagnose early cancers associated with particular PGVs, and disparities in patient access to genetic tests are well described.Similarly, despite dozens of studies demonstrating that detected circulating tumor DNA (ctDNA) after curative intention therapy of different cancer types is a highly accurate biomarker that predicts recurrence, the major organizations that publish guidelines for cancer monitoring after curative intention therapy recommend against using ctDNA assays to detect minimal residual disease and thereby predict recurrence for all solid tumor malignancies.Here, the primary reasons that these genetic tests are considered to lack proven clinical utility and the primary evidence suggesting that a broader definition of clinical utility should be considered are discussed. By expanding the definition of clinical utility, many patients will benefit from the information gained from having these genetic tests.

Precision oncology comes of age.

ABSTRACT: Each cancer has a unique fingerprint, and precision oncology can be used to more effectively fight malignancies. The identified genes, expressed RNA, and proteins expressed in patients' cancers are now used routinely to predict prognosis and inform treatment recommendations. This article describes how malignancies develop and some of the targeted drugs that can be used against them.

Why it is our responsibility to speak out for a universal vaccination mandate.

Patients with cancer are among the most likely to suffer life-threatening complications should they contract coronavirus disease 2019, yet despite encouragement from their oncologists, many continue to refuse to be vaccinated. On behalf of our patients, I believe that oncologists should now exhort our elected government to fulfill its most fundamental responsibility-protecting Americans from existential threats-by enacting either an emergency executive order or universal vaccination legislation and then by helping the rest of the world to vaccinate without delay.

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).

The implications of BRCA loss of heterozygosity (LOH) and deficient mismatch repair gene (dMMR) expression in the breast cancer of a patient with both inherited breast and ovarian cancer syndrome (BRCA2) and Lynch syndrome (MLH1).

BACKGROUND: BRCA germline pathogenic variants represent the most common inherited mechanism predisposing individuals to breast cancer, while germline pathogenic variants in one of the mismatch repair (MMR) genes represent the most common colon cancer-predisposing inherited syndrome, known as the Lynch syndrome (LS). Individuals who harbor pathogenic germline variants for both syndromes are extremely rare. Germline testing is now done routinely for patients with breast cancer and MMR testing is recommended for nearly all patients diagnosed with colon or rectal cancer (Benson et al in NCCN clinical practice guidelines in oncology (NCCN guidelines) colon cancer (Version 4.2019-November 8, 2019). www.NCCN.org, Gradishar et al in NCCN clinical practice guidelines in oncology (NCCN guidelines) breast cancer (Version 3.2019-September 6, 2019).www.NCCN.org). We report a patient with germline mutations in both BRCA2 and the MMR gene MLH1 who developed breast cancer. The breast cancer showed loss of heterozygosity (LOH) in BRCA2 (the molecular hallmark of cancers related to inheritance of a BRCA alteration) and was also deficient in mismatch repair gene protein expression (dMMR), the hallmark of LS-related cancers. We discuss the possible mechanisms of transformation that would explain the finding that the tumor showed both BRCA2 LOH and was dMMR, each of which would generally be considered a gatekeeper event for transformation of normal cells to malignancy. RESULTS: This report describes a patient with molecularly diagnosed breast and ovarian cancer syndrome (BRCA2) and LS. Next generation sequencing (NGS) and immunohistochemical (IHC) testing demonstrated her breast cancer to show BRCA2 LOH and to be dMMR. CONCLUSION: The patient presented represents the first reported case where both next generation sequencing (NGS) for BRCA LOH and MMR IHC testing of her breast cancer were performed and underscores the importance of using NGS including the reported mutational allelic frequency (MAF) and IHC use to predict the likely responsiveness to the recently approved PARP inhibitors and checkpoint inhibitor therapies (Robson et al in N Engl J Med 377:523-533, 2017, Lemery et al in 377(15):1409-1412, https://doi.org/10.1056/NEJMp1709968, 2017), key because the gatekeeper transforming event for tumors related to inherited cancer syndromes is loss of normal tumor suppressor gene (TSG) protein expression.

Neuromuscular ultrasound for taxane peripheral neuropathy in breast cancer.

BACKGROUND: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent. METHODS: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD). RESULTS: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm2 smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R2 0.30; P = .04). CONCLUSIONS: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN.

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.

The Importance of Distinguishing Sporadic Cancers from Those Related to Cancer Predisposing Germline Mutations.

Choosing the optimal therapy for a patient's cancer has long been based on whether the cancer demonstrates a predictive marker of efficacy. The U.S. Food and Drug Administration (FDA) has now approved use of a targeted therapy based solely on tumor molecular markers (pembrolizumab for tumors with deficient mismatch repair [MMR] and high microsatellite instability [MSI]) and approved another therapy based solely on a germline mutation as the predictive marker of benefit (olaparib for BRCA carriers with ovarian or breast cancer) [New Engl J Med 2017;377:1409-1412, N Engl J Med 2012;366:1382-1392, N Eng J Med 2017;377:523-533].Here, a patient is presented with a molecular diagnosis of Lynch syndrome and with breast cancer. Yet the breast cancer showed proficient expression of the same MMR gene found to be mutated in her germline testing. The case underscores the importance of tumor testing for MMR and MSI and of not assuming that the tumor is related to the Lynch syndrome rather than being sporadic. This is particularly true in patients with cancers (e.g., breast cancer) whose association with Lynch syndrome is not well established.The case presented also underscores the importance of considering next-generation sequencing of the tumor when the therapies approved are based on a germline mutation being the predictive marker. For example, the FDA-approved use of the PARP inhibitor olaparib is for ovarian or breast cancers in patients harboring a BRCA germline mutation [N Engl J Med 2012;366:1382-1392, N Eng J Med 2017;377:523-533]. Yet patients with tumors lacking BRCA loss of heterozygosity (LOH) or lacking other evidence of probable loss of normal BRCA gene product expression might be less likely to benefit from PARP inhibitor therapy, because the efficacy of PARP inhibitor therapy in patients with germline BRCA mutations would likely be predicated upon BRCA LOH in their tumors. KEY POINTS: Cancers in patients with germline mutations may be sporadic and unrelated to the germline mutation.Lynch syndrome is due to a germline mutated mismatch repair (MMR) gene. Cancers resulting from the germline MMR gene mutation as the predisposing event would be expected to be MMR deficient (dMMR) and microsatellite instability high (MSI-H). Sporadic cancers in patients with Lynch syndrome would be expected to be MMR proficient or microsatellite stable.Pembrolizumab is only approved for solid tumors demonstrating dMMR/MSI-H. Thus, whether the cancer tissue of origin is clearly associated with Lynch syndrome or not yet clearly established as a Lynch syndrome-related cancer (e.g., breast cancer), establishing the tumor to be dMMR/MSI-H is necessary to predict possible benefit and endorse the use of pembrolizumab.Ovarian cancers that develop in BRCA germline mutation carriers are so often related to the inherited mutated BRCA as the predisposing factor that testing the tumor for the footprint of BRCA-related ovarian cancer (BRCA loss of heterozygosity) is not necessary for use of the PARP inhibitor therapy olaparib. Future studies that include tumor evaluation for normal BRCA expression or surrogates of normal BRCA gene product expression might help determine which patients harboring a germline BRCA mutation are most likely to benefit from PARP inhibitor therapy.