Research Spotlight

Bardia, A., Tolaney, S.M., Punie, K., Loirat, D., Oliveira, M., Kalinsky, K., Zelnak, A., Aftimos, P., Dalenc, F., Sardesai, S., Hamilton, E., Sharma, P., Recalde, S., Gil, E.C., Traina, T., O’Shaughnessy, J., Cortes, J., Tsai, M., Vahdat, L., Diéras, V., Carey, L.A., Rugo, H.S., Goldenberg, D.M., Hong, Q., Olivo, M., Itri, L.M. and Hurvitz, S.A. (2021). “Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.” Ann Oncol Jun 8;S0923-7534(21)02047-0. [Epub ahead of print].

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BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician’s choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.

Packer, M. (2021). “Pitfalls in Using Estimated Glomerular Filtration Rate Slope as a Surrogate for the Effect of Drugs on the Risk of Serious Adverse Renal Outcomes in Clinical Trials of Patients With Heart Failure.” Circ Heart Fail 14(6): e008537.

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The rate of decline in eGFR is commonly assessed by the measurement of eGFR slope, but this calculation is fraught with methodological difficulties. Estimation of slope relies in statistical models that make assumptions about linearity and are typically skewed by values measured late in the course of follow-up. [No abstract; excerpt from article].

Banchereau, R., Leng, N., Zill, O., Sokol, E., Liu, G., Pavlick, D., Maund, S., Liu, L.F., Kadel, E., 3rd, Baldwin, N., Jhunjhunwala, S., Nickles, D., Assaf, Z.J., Bower, D., Patil, N., McCleland, M., Shames, D., Molinero, L., Huseni, M., Sanjabi, S., Cummings, C., Mellman, I., Mariathasan, S., Hegde, P. and Powles, T. (2021). “Molecular determinants of response to PD-L1 blockade across tumor types.” Nat Commun 12(1): 3969.

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Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1(+) tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.

Singapura, P., Ma, T.W., Sarmast, N., Gonzalez, S., Durand, F., Maiwall, R., Nadim, M.K., Fullinwider, J., Saracino, G., Francoz, C., Sartin, R., Trotter, J. and Asrani, S.K. (2021). “Estimating glomerular filtration rate in cirrhosis using creatinine- and cystatin C- based equations: systematic review and meta-analysis.” Liver Transpl Jun 18. [Epub ahead of print].

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BACKGROUND AND AIMS: Accurate estimation of kidney function in cirrhosis is crucial for prognosis and decisions regarding dual organ transplantation. Several estimating glomerular filtration rate (GFR) equations are used, however, most overestimate kidney function. APPROACH AND RESULTS: We performed a systematic review/meta-analysis to assess the performance of creatinine and cystatin C-based GFR estimating (eGFR) equations as compared to measured GFR (mGFR) in patients with cirrhosis. Standardized mean difference (SMD) of each eGFR equation was compared to mGFR. Twenty-five studies (n= 4,565, 52.0years, 37.0% female) comprising 18 equations met the inclusion criteria. All GFR: Creatinine-based equations overestimated GFR (SMD 0.51, 95% CI0.31-0.71) and cystatin C-based equations underestimated GFR (SMD -0.3, 95% CI-0.6- -0.02). Equations based on both creatinine and cystatin C were the least biased (SMD -0.14, 95% CI -0.46-0.18). CKD-Epi-sCr-CysC was the least biased but had low precision and underestimated GFR by -3.6 ml/min/1.73m(2) (95% CI -17.4-10.3). GFR<60ml/min/1.73m(2) : All equations significantly overestimated GFR (+21.7 ml/min/1.73m(2) , 95% CI17.7-25.7); of these, CKD-Epi-CysC (10.3 ml/min/1.73m(2) , 95% CI2.1-18.4) and GFR Assessment in Liver disease (GRAIL) (12.6 ml/min/1.73m(2) , 95%CI 7.2-18.0) were the least biased followed by Royal Free Hospital (RFH) (15 ml/min/1.73m(2) , 95%CI 5.5-24.6) and MDRD-6 (15.7 ml/min/1.73m(2) , 95%CI 10.6-20.8).; however there was overlap in the precision of estimates and studies were limited. Ascites: Overestimation of GFR was common (+8.3 ml/min/1.73m(2) , 95%CI -3.1-19.7). CONCLUSION: CKD-Epi-sCr-CysC may be acceptable across the spectrum of GFR. However, overestimation of GFR by 10-20 ml/min/1.73m(2) is common in patients with cirrhosis with most equations, especially in conjunction with ascites and/or kidney dysfunction. There is wide overlap in confidence intervals/precision. A tailored approach is required based on clinical scenario, especially for decisions regarding dual organ transplantation.

Lago-Hernandez, C., Nguyen, N.H., Khera, R., Loomba, R., Asrani, S.K. and Singh, S. (2021). “Cost-Related Nonadherence to Medications Among US Adults With Chronic Liver Diseases.” Mayo Clin Proc Jun 10;S0025-6196(21)00255-X. [Epub ahead of print].

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OBJECTIVE: To estimate the prevalence, risk factors, and consequences of cost-related medication nonadherence (CRN) in individuals with chronic liver diseases (CLDs) in the United States. PATIENTS AND METHODS: Using the National Health Interview Survey from January 1, 2014, to December 31, 2018, we identified individuals with CLDs. Using complex weighted survey analysis, we obtained national estimates and risk factors for CRN and its association with cost-reducing behaviors and measures of financial toxicity. We evaluated the association of CRN with unplanned health care use, adjusting for age, sex, race/ethnicity, insurance, income, education, and comorbid conditions. RESULTS: Of 3237 respondents (representing 4.6 million) US adults with CLDs, 813 (representing 1.2 million adults, or 25%; 95% CI, 23% to 27%) reported CRN, of whom 68% (n=554/813) reported maladaptive cost-reducing behaviors. Younger age, female sex, low income, and multimorbidity were associated with a higher prevalence of CRN. Compared with patients without CRN, patients experiencing CRN had 5.1 times higher odds of financial hardship from medical bills (adjusted odds ratio [aOR], 5.05; 95% CI, 3.73 to 6.83) and 2.9 times higher odds of food insecurity (aOR, 2.85; 95% CI, 2.02 to 4.01). The CRN was also associated with 1.5 times higher odds of emergency department visits (aOR, 1.46; 95% CI, 1.11 to 1.94). CONCLUSION: We observed a high prevalence of CRN and associated consequences such as high financial distress, financial hardship from medical bills, food insecurity, engagement in maladaptive cost-reducing strategies, increased health care use, and work absenteeism among patients with CLD. These financial determinants of health have important implications in the context of value-based care.