Tissue tumor mutational burden (tTMB) is calculated to aid in cancer treatment selection. High tTMB predicts a favorable response to immunotherapy in patients with non-small cell lung cancer. Blood TMB (bTMB) from circulating tumor DNA is reported to have similar predictive power and has been proposed as an alternative to tTMB. Across many studies not only are tTMB and bTMB not concordant but also as reported previously by our group predict conflicting outcomes. This implies that bTMB is not a substitute for tTMB, but rather a composite index that may encompass tumor heterogeneity. Here, we provide a thorough overview of the predictive power of TMB, discuss the use of tumor heterogeneity alongside TMB to predict treatment response and review several methods of tumor heterogeneity assessment. Furthermore, we propose a hypothetical method of estimating tumor heterogeneity and touch on its clinical implications.
BackgroundImmune checkpoint inhibitors have revolutionized care for a number of different cancer types. For colorectal cancer (CRC), a leading cause of cancer-related death in the United States, programmed cell death protein 1 (PD-1) inhibition is a treatment option for certain subsets of patients. High microsatellite instability (MSI-H) tumors are immunogenic, and thus PD-1 inhibition is first-line treatment. Anti-PD-1 therapy is generally not utilized for microsatellite stable (MSS) patients. Tumor mutational burden (TMB) is another predictive biomarker for immunotherapy response in all solid tumors. Here we present the case of a patient with MSS, TMB-H CRC resistant to multiple lines of chemotherapy, who responded to anti-PD-1 monotherapy.MethodsCase presentation.ResultsA 64-year-old man with a family history significant for colon cancer was diagnosed with colorectal cancer, revealed to be moderately differentiated mucinous adenocarcinoma (stage IIIC) on biopsy. A tissue-based comprehensive genomic profiling of the cancer showed KRASG12D and ERBB2 amplification, microsatellite-stable, and TMB of 11mut/mB (FoundationOne). The patient progressed on multiple lines of therapy with multiple metastatic sites, and was briefly put under home hospice with diffuse abdominal pain and weight loss. The patient was started on pembrolizumab monotherapy, around 3.5 years after initial presentation. After five months on pembrolizumab, imaging showed significant improvement in pulmonary, hepatic, adrenal, and retroperitoneal metastases and the patient demonstrated partial response to treatment according to RECIST 1.1 criteria. The patient's carcinoembryonic antigen (CEA) levels had decreased from 45 ng/mL at treatment initiation to 2.8 ng/mL, and ctDNA analysis showed a blood TMB decrease from 31.58 mut/mB at treatment initiation to .96 mut/mB (figure 1), accompanied by decreases in the variant allele frequencies of the five most prevalent variants at the time of treatment initiation (Guardant 360). The patient's pain had nearly resolved by this point and pain medications were tapered off.ConclusionsThis case demonstrates the existence of a subset of CRC patients who are MSS but TMB-H and may respond to immune checkpoint blockade. Comprehensive genomic profiling must be utilized in order to not miss this subset of patients. The mechanism of response in this subset of patients is unknown but warrants further exploration. Further studies should clarify the mechanism and likelihood of response to immunotherapy in MSS, TMB-H CRC patients, as this is critical to providing effective treatment for this subset.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 631 Figure 1Carcinoembryonic antigen (CEA) and blood tumor mutational burden (TMB) levels through six cycles of treatment with pembrolizumab
e21061 Background: To evaluate the role of double lung transplantation (DLT) for lung cancer, the survival outcomes of patients who underwent DLT for lung cancer and the incidence of lung cancer after DLT were assessed. Methods: Data from case series reported in the literature were pooled and collected from the Organ Procurement Transplantation Network (OPTN) and the International Society of Heart and Lung Transplantation (ISHLT) registries. We evaluated the recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) of patients who underwent DLT for lung cancer. Moreover, the incidence and OS of post-transplant lung cancer in patients who received transplants for the non-cancerous disease were examined. Results: Regarding patients who underwent DLT for lung cancer, in the pooled (n = 19), OPTN (n = 15), and ISHLT (n = 25) data, 5-year RFS was 52.6%, 66.7%, and 80.0%, and 5-year OS was 57.9%, 26.7%, and 36.0%, respectively. The median CSS was 48.0 (range, 6.0–144.0), 27.7 (range, 0.2–66.6), and 24.0 (range, 0.1–145.1) months. Additionally, the application of cardiopulmonary bypass was associated with lower tumor recurrence in the pooled data (p = 0.004). The incidence and 5-year OS post-transplant lung cancer in patients who underwent DLT for the non-cancerous disease were 0.8% and 47.3% in the OPTN data and 0.6% and 50.7% in the ISHLT data, respectively. Conclusions: We demonstrated that reasonable survival outcomes can be achieved with DLT in patients with bilateral lung cancer. Further studies are required to evaluate the risk of post-transplant lung cancer in patients undergoing DLT for bilateral lung cancer.
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