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Simple Summary: Cholangiocarcinoma is characterized by a very poor outcome and SerpinB3, a serine protease inhibitor, has recently been found to play a relevant role in malignant transformation in different cancers. The aim of this study was to analyze the expression of this biomarker in the serum and surgical specimens of cholangiocarcinoma in relation to clinical outcome. High levels of SerpinB3/4 were detected in tumoral tissue in 12.2% of CCA, which were characterized by a more advanced TNM stage and lower overall patient survival, independently of CCA subclass. In addition, patients who had detectable free or IgM-linked SerpinB3/4 in serum showed poorer survival. In conclusion, the present study provides evidence that SerpinB3/4, both in the serum and in tumoral tissue, could be considered a useful biomarker to identify the small subgroup of CCA patients with more aggressive tumor biology and dismal prognosis. Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; p = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8—Not Estimable, NE) vs. 2.4 (1.8–3.4) years; p = 0.0007; extrahepatic CCA: median 0.8 (0.2—NE) vs. 2.2 (1.5–5.4) years; p = 0.011). Vascular invasion (p = 0.027) and SerpinB3/4 scores (p = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, p = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, p = 0.0026, for SerpinB3/4–IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy with atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab has recently become the preferred first-line treatment for advanced hepatocellular carcinoma (HCC). Lenvatinib was initially approved as a first-line treatment, but little is known about its effectiveness following immunotherapy. The aim of our retrospective study was to characterize the clinical outcomes with lenvatinib following immunotherapy treatment. In our cohort of 53 patients, the median progression free survival was 3.7 months, and the median overall survival was 12.8 months from lenvatinib initiation. Multivariate analysis demonstrated race, gender, and Child Pugh Class as significant predictors of survival outcomes and BMI as well as distant metastasis as predictors of progression free survival. This study supports the efficacy of lenvatinib following immunotherapy and validates the use of lenvatinib as a second-line therapy following progression on immunotherapy in patients with advanced HCC. Background: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear. Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan–Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0. Results: We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2–6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7–19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis. Discussion: Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial. [ABSTRACT FROM AUTHOR]

Aberrantly methylated genes contribute to the landscape of epigenetic alterations in colorectal adenocarcinoma. The global CpG Island methylator phenotype (CIMP) and individually methylated genes are potential prognostic/predictive biomarkers. Research suggests an association between methylated DCR1 (mDCR1) and lack of benefit with irinotecan (IFL) treatment. We assessed the association between DCR1 methylation status and survival in patients receiving adjuvant fluorouracil/ leucovorin (5-FU/LV) or IFL. We analysed data from patients with stage III colon adenocarcinoma randomly assigned to adjuvant 5-FU/LV or IFL in CALGB 89803 (Alliance). The primary endpoint was overall survival (OS), and the secondary endpoint was disease-free survival (DFS). Using tumour sample DNA, we evaluated the association between survival, DCR1 methylation status, and molecular subgroups (BRAF, KRAS, mismatch repair status, CIMP status) using Kaplan–Meier estimator and Cox proportional hazard model. mDCR1 was observed in 221/400 (55%) colon cancers. Histopathologic features were similar between mDCR1 and unmethylated DCR1 (unDCR1) colon cancers. There was no difference in OS (p = 0.83) or DFS (p = 0.85) based on DCR1 methylation status. There was no association between methylation status and response to IFL. In patients with unDCR1 and KRAS-wildtype tumours, those who received IFL had a nearly two-fold worse DFS compared to patients who received 5-FU/LV (HR = 1.85, 95% CI (0.97–3.53, p = 0.06). This relationship was not notable among other subgroups. In stage III colon cancer patients, mDCR1 status did not associate with response to irinotecan. Larger studies may suggest an association between the iridocene response and molecular subgroups. [ABSTRACT FROM AUTHOR]

Simple Summary: Management of hepatocellular carcinoma is a rapidly evolving field, with atezolizumab-bevacizumab recently becoming standard of care after showing survival benefit over sorafenib. However, all clinical trials evaluating drugs approved in the second line setting, such as cabozantinib, have been evaluated following progression on sorafenib, not immunotherapy. We sought to determine if cabozantinib is a viable option for patients after progression on immunotherapy. We conducted a retrospective analysis of patients seen at our institution who had disease progression on immunotherapy and subsequently received cabozantinib, reporting patient survival and tolerance of treatment. We found that patients had a median progression free survival of 2.1 months and median overall survival of 7.7 months, and most patients had a manageable side effect profile, suggesting that cabozantinib is a viable treatment option following progression on immunotherapy. (1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010–2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan–Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3–3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3–14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy. [ABSTRACT FROM AUTHOR]

Background Combination irinotecan and cetuximab is approved for irinotecan-refractory metastatic colorectal cancer (mCRC). It is unknown if adding bevacizumab improves outcomes. Patients and Methods In this multicenter, randomized, double-blind, placebo-controlled phase II trial, patients with irinotecan-refractory RAS- wildtype mCRC and no prior anti-EGFR therapy were randomized to cetuximab 500 mg/m2, bevacizumab 5 mg/kg, and irinotecan 180 mg/m2 (or previously tolerated dose) (CBI) versus cetuximab, irinotecan, and placebo (CI) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). Results The study closed early after the accrual of 36 out of a planned 120 patients due to changes in funding. Nineteen patients were randomized to CBI and 17 to CI. Baseline characteristics were similar between arms. Median PFS was 9.7 versus 5.5 months for CBI and CI, respectively (1-sided log-rank P =.38; adjusted hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.25-1.66). Median OS was 19.7 versus 10.2 months for CBI and CI (1-sided log-rank P =.02; adjusted HR = 0.41; 95% CI, 0.15-1.09). ORR was 36.8% for CBI versus 11.8% for CI (P =.13). Grade 3 or higher AEs occurred in 47% of patients receiving CBI versus 35% for CI (P =.46). Conclusion In this prematurely discontinued trial, there was no significant difference in the primary endpoint of PFS between CBI and CI. There was a statistically significant improvement in OS in favor of CBI compared with CI. Further investigation of CBI for the treatment of irinotecan-refractory mCRC is warranted. Clinical Trial Registration: NCT02292758 [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the association between self‐identified race and overall survival (OS), progression‐free survival (PFS), and response to therapy among patients enrolled in the randomized Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial. Methods: Patients with advanced or metastatic colorectal cancer who were enrolled in the CALGB/SWOG 80405 trial were identified by race. On the basis of covariates (treatment arm, KRAS status, sex, age, and body mass index), each Black patient was exact matched with a White patient. The association between race and OS and PFS was examined using a marginal Cox proportional hazard model for matched pairs. The interaction between KRAS status and race was tested in the model. The association between race and response to therapy and adverse events were examined using a marginal logistic regression model. Results: In total, 392 patients were matched and included in the final data set. No difference in OS (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.73‐1.16), PFS (HR, 0.97; 95% CI, 0.78‐1.20), or response to therapy (odds ratio [OR], 1.00; 95% CI, 0.65‐1.52) was observed between Black and White patients. Patients with KRAS mutant status (HR, 1.31; 95% CI, 1.02‐1.67), a performance statusscore of 1 (reference, a performance status of 0; HR, 1.49; 95% CI, 1.18‐1.88), or ≥3 metastatic sites (reference, 1 metastatic site; HR, 1.67; 95% CI, 1.22‐2.28) experienced worse OS. Black patients experienced lower rates and risk of grade ≥3 fatigue (6.6% vs 13.3%; OR, 0.46; 95% CI, 0.24‐0.91) but were equally likely to be treated with a dose reduction (OR, 1.09; 95% CI, 0.72‐1.65). Conclusions: No difference in OS, PFS, or response to therapy was observed between Black patients and White patients in an equal treatment setting of the CALGB/SWOG 80405 randomized controlled trial. Lay Summary: Despite improvements in screening and treatment, studies have demonstrated worse outcomes in Black patients with colorectal cancer.The purpose of this study was to determine whether there was a difference in cancer‐specific outcomes among Black and White patients receiving equivalent treatment on the CALGB/SWOG 80405 randomized clinical trial.In this study, there was no difference in overall survival, progression‐free survival, or response to therapy between Black and White patients treated on a clinical trial.These findings suggest that access to care and differences in treatment may be responsible for racial disparities in colorectal cancer. In a secondary analysis of the CALGB/SWOG 80405 randomized clinical trial, there was no difference in overall survival, progression‐free survival, or response to therapy between matched Black patients and White patients with advanced or metastatic colorectal cancer. Because racial disparities in metastatic colorectal cancer survival were not seen in an equal treatment setting, differences in access to care and treatment delivery may be responsible for the racial disparities observed in epidemiological studies. [ABSTRACT FROM AUTHOR]

Background: Hand‐foot skin reaction (HFSR) is the most common regorafenib‐induced adverse event and is in need of effective prevention and palliation. Materials and Methods: The Regorafenib Dose Optimization Study (ReDOS), a four‐arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. Results: Sixty‐one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p =.03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p =.35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p =.02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p =.12). Patient‐reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol‐induced adverse events were reported. Conclusion: Preemptive clobetasol might lessen regorafenib‐induced hand‐foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. Implications for Practice: Regorafenib causes hand‐foot skin reactions. Preemptive clobetasol, a high‐potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients. Hand‐foot skin reaction is a common regorafenib‐induced adverse event. This article reports on the use of topical clobetasol and its role when administered preventively, before a skin reaction occurs. [ABSTRACT FROM AUTHOR]

Background The American Joint Committee on Cancer staging and other prognostic tools fail to account for stage-independent variability in outcome. We developed a prognostic classifier adding Immunoscore to clinicopathological and molecular features in patients with stage III colon cancer. Methods Patient (n = 559) data from the FOLFOX arm of adjuvant trial NCCTG N0147 were used to construct Cox models for predicting disease-free survival (DFS). Variables included age, sex, T stage, positive lymph nodes (+LNs), N stage, performance status, histologic grade, sidedness, KRAS/BRAF , mismatch repair, and Immunoscore (CD3+, CD8+ T-cell densities). After determining optimal functional form (continuous or categorical) and within Cox models, backward selection was performed to analyze all variables as candidate predictors. All statistical tests were two-sided. Results Poorer DFS was found for tumors that were T4 vs T3 (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.19 to 2.60; P  = .004), right- vs left-sided (HR = 1.52, 95% CI = 1.14 to 2.04; P  = .005), BRAF V600E (HR = 1.74, 95% CI = 1.26 to 2.40; P  < .001), mutant KRAS (HR = 1.66, 95% CI = 1.08 to 2.55; P  = .02), and low vs high Immunoscore (HR = 1.69, 95% CI = 1.22 to 2.33; P = .001) (all P  <  .02). Increasing numbers of +LNs and lower continuous Immunoscore were associated with poorer DFS that achieved significance (both P s<  .0001). After number of +LNs, T stage, and BRAF/KRAS , Immunoscore was the most informative predictor of DFS shown multivariately. Among T1–3 N1 tumors, Immunoscore was the only variable associated with DFS that achieved statistical significance. A nomogram was generated to determine the likelihood of being recurrence-free at 3 years. Conclusions The Immunoscore can enhance the accuracy of survival prediction among patients with stage III colon cancer. [ABSTRACT FROM AUTHOR]

Marine omega‐3 polyunsaturated fatty acids (MO3PUFAs) have anticancer properties and may improve colon cancer survival. However, it remains unknown whether the benefit differs by tumor molecular subtype. We examined data from a phase III randomized trial of FOLFOX or FOLFOX + cetuximab among 1,735 stage III colon cancer patients who completed a dietary questionnaire at enrollment. Multivariable hazard ratios and 95% confidence intervals (CIs) were calculated for the association between MO3PUFA and disease‐free survival (DFS) and overall survival according to KRAS and BRAFV600E mutations and DNA mismatch repair (MMR) status. Higher MO3PUFA intake was associated with improved 3‐year DFS for KRAS wild‐type tumors (77% vs. 73%; HR: 0.84; 95% CI: 0.67–1.05) but not KRAS‐mutant tumors (64% vs. 70%; HR: 1.30; 95% CI: 0.97–1.73; Pinteraction = 0.02). Similar heterogeneity was found by MMR (Pinteraction = 0.14): higher MO3PUFA was associated with better 3‐year DFS for tumors with deficient MMR (72% vs. 67%) but not proficient MMR (72% vs. 72%). No heterogeneity was found by BRAFV600E mutation. Similar findings were obtained for overall survival. In conclusion, we found a suggestive beneficial association between higher MO3PUFA intake and improved survival among stage III colon cancer patients with wild‐type KRAS and deficient MMR. Given the relatively small number of cases with tumor molecular assessments, further studies, preferably through pooled analyses of multiples cohorts, are needed to validate our findings. What's new? Consumption of fish oil or related products containing marine omega‐3 polyunsaturated fatty acid (MO3PUFA) has long been associated with health benefits but effects on cancer survival remain unclear. Here the authors find tentative evidence that MO3PUFA supplementation in patients with stage III colon cancer is associated with better survival, but the benefit was restricted to tumors lacking mutations in the KRAS proto‐oncogene and arising from the microsatellite instability pathway, a finding with possible implications for improving patient care. [ABSTRACT FROM AUTHOR]

Background: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes. Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS). Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69-0.99] and 0.76 (95% CI, 0.63-0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03). Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes. [ABSTRACT FROM AUTHOR]

Lessons Learned: Trifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5‐fluorouracil refractory tumors.FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first‐line therapy. Background: Patients with advanced biliary tract carcinoma (BTC) refractory to first‐line therapy lack an established second‐line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine‐sensitive and ‐resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC. Methods: Patients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression‐free survival (PFS), and toxicity. Results: Of 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted. Conclusion: FTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC. [ABSTRACT FROM AUTHOR]