Peritoneal metastases from primary appendiceal and colorectal carcinomas demonstrate distinct molecular identities on comprehensive tumor analysis.

BACKGROUND AND OBJECTIVES: Published data comparing peritoneal metastases from appendiceal cancers (pAC) and colorectal cancers (pCRC) remain sparse. We compared pAC and pCRC using comprehensive tumor profiling (CTP). METHODS: CTP was performed, including next-generation sequencing and analysis of copy number variation (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). RESULTS: One hundred thirty-six pAC and 348 pCRC samples underwent CTP. The cohorts' age and gender were similar. pCRC demonstrated increased pathogenic variants (PATHs) in APC (48% vs. 3%, p < 0.01), ARID1A (12% vs. 2%, p < 0.01), BRAF (12% vs. 2%, p < 0.01), FBXW7 (7% vs. 2%, p < 0.01), KRAS (52% vs. 41%, p < 0.05), PIK3CA (15% vs. 2%, p < 0.01), and TP53 (53% vs. 23%, p < 0.01), and decreased PATHs in GNAS (8% vs. 31%, p < 0.01). There was no difference in CNV, fusion rate, or MSI. Median TMB was higher in pCRC (5.8 vs. 5.0 mutations per megabase, p = 0.0007). Rates of TMB-high tumors were similar (pAC 2.1% vs. pCRC 9.0%, p = 0.1957). pCRC had significantly more TMB-high tumors at lower thresholds. CONCLUSIONS: Despite a reduced overall TMB, pAC demonstrated mutations distinct from those seen in pCRC. These may serve as discrete biomarkers for future study.

Impact of Sociodemographic Disparities and Insurance Status on Survival of Patients with Early-Onset Colorectal Cancer.

BACKGROUND: Low socioeconomic status (SES) has been linked to worse survival in patients with colorectal cancer (CRC); however, the impact of SES on early-onset CRC remains undescribed. MATERIALS AND METHODS: Retrospective analysis of data from the National Cancer Database (NCDB) between 2004 and 2016 was conducted. We combined income and education to form a composite measure of SES. Logistic regression and χ2 testing were used to examine early-onset CRC according to SES group. Survival rates and Cox proportional hazards models compared stage-specific overall survival (OS) between the SES groups. RESULTS: In total, 30,903 patients with early-onset CRC were identified, of whom 78.7% were White; 14.5% were Black. Low SES compared with high SES patients were more likely to be Black (26.3% vs. 6.1%) or Hispanic (25.3% vs. 10.5%), have T4 tumors (21.3% vs. 17.8%) and/or N2 disease (13% vs. 11.1%), and present with stage IV disease (32.8% vs. 27.7%) at diagnosis (p < .0001, all comparisons). OS gradually improved with increasing SES at all disease stages (p < .001). In stage IV, the 5-year survival rate was 13.9% vs. 21.7% for patients with low compared with high SES. In multivariable analysis, SES (low vs. high group; adjusted hazard ratio [HRadj ], 1.35; 95% confidence interval [CI], 1.26-1.46) was found to have a significant effect on survival (p < .0001) when all of the confounding variables were adjusted. Insurance (not private vs. private; HRadj , 1.38; 95% CI, 1.31-1.44) mediates 31% of the SES effect on survival. CONCLUSION: Patients with early-onset CRC with low SES had the worst outcomes. Our data suggest that SES should be considered when implementing programs to improve the early detection and treatment of patients with early-onset CRC. IMPLICATIONS FOR PRACTICE: Low socioeconomic status (SES) has been linked to worse survival in patients with colorectal cancer (CRC); however, the impact of SES on early-onset CRC remains undescribed. In this retrospective study of 30,903 patients with early-onset CRC in the National Cancer Database, a steady increase in the yearly rate of stage IV diagnosis at presentation was observed. The risk of death increased as socioeconomic status decreased. Race and insurance status were independent predictors for survival. Implementation of programs to improve access to care and early diagnostic strategies among younger adults, especially those with low SES, is warranted.

Early-onset pancreatic cancer: an institutional series evaluating end-of-life care.

PURPOSE: Little is known about the use of palliative and hospice care and their impact on healthcare utilization near the end of life (EOL) in early-onset pancreatic cancer (EOPC). METHODS: Patients with EOPC (≤ 50 years) were identified using the institutional tumor registry for years 2011-2018, and demographic, clinical, and rates of referral to palliative and hospice services were obtained retrospectively. Predictors of healthcare utilization, defined as use of ≥ 1 emergency department (ED) visit or hospitalization within 30 days of death, place of death (non-hospital vs. hospital), and time from last chemotherapy administration prior to death, were assessed using descriptive, univariable, and multivariable analyses including chi-square and logistic regression models. RESULTS: A total of 112 patients with EOPC with a median age of 46 years (range, 29-50) were studied. Forty-four percent were female, 28% were Black, and 45% had metastatic disease. Fifty-seven percent received palliative care at a median of 7.8 weeks (range 0-265) following diagnosis. The median time between last chemotherapy and death was 7.9 weeks (range 0-102). Seventy-four percent used hospice services prior to death for a median of 15 days (range 0-241). Rate of healthcare utilization at the EOL was 74% in the overall population. Black race and late use of chemotherapy were independently associated with increase in ED visits/hospitalization and hospital place of death. CONCLUSIONS: Although we observed early referrals to palliative care among patients with newly diagnosed EOPC, short duration of hospice enrollment and rates of healthcare utilization prior to death were substantial.

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma.

BACKGROUND AND OBJECTIVES: Peritoneal metastases (PM) from primary colorectal cancer (pCRC) are associated with poor outcomes; however, molecular differences are not well defined. METHODS: We compared unpaired tumor profiles of patients with pCRC and PM from Caris Life Sciences. Testing included next-generation sequencing of 592 genes, microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were test-defined as pathogenic (PATH). RESULTS: Six hundred seventeen pCRC and 348 PM patients had similar gender (55% male) and age (median 59). PATHs were similar between PM and pCRC in KRAS, BRAF, SMAD2, SMAD4, and PTEN. pCRC PATHs were increased in APC (76% vs 48%, P < .01), ARID1A (29% vs 12%, P < .05), TP53 (72% vs 53%, P < .01), PIK3CA (22% vs 15%, P < .05), and FBXW7 (13% vs 7%, P < .01) compared with PM. Mucinous PM had more PATHs in GNAS (19% vs 8%, P = .032) while nonmucinous PM had more PATHs in BRAF (13% vs 8%, P = .027). Right-sided PM had decreased PATHs in APC (39% vs 68%, P < .0001), ARID1A (7% vs 38%, P < .004), and TP53 (48% vs 65%, P = .033) while there were no difference for left-sided PM. Nine percent of pCRC and 6% of PM were MSI-high (P = NS). There was no difference in TMB-high, TMB-intermediate, or TMB-low between PM and pCRC. CONCLUSIONS: PM have similar rates of KRAS mutation with increased PATHs in GNAS (mucinous) and BRAF (nonmucinous) compared to pCRC. No differences in MSI or TMB were identified between PM and pCRC tumors. These findings inform future study into the molecular profile of PM.

Advances in borderline resectable pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is one of the most lethal cancers in oncology. Pancreatic cancer is the third most common cause of cancer-related mortality in the United States. As the years have progressed, the importance of a multidisciplinary and multimodal approach to pancreatic cancer care has been recognized and is now recommended in all major society guidelines. A subset of pancreatic cancer, borderline resectable pancreatic cancer (BRPC), has emerged as a distinct clinical entity for which specialized treatment plans are now being developed. The medical oncologist, surgical oncologist, and radiation oncologist must work jointly to help deliver the best clinical outcome for the patient with pancreatic cancer. In this discussion, we describe the current state of surgical, locoregional therapies and systemic therapy in BRPC.

Frequency of unplanned surgery in patients with stage IV colorectal cancer receiving palliative chemotherapy with an intact primary: An analysis of SEER-Medicare.

BACKGROUND AND OBJECTIVES: Stage IV colorectal cancer is often treated with palliative chemotherapy with the primary tumor in place. Low rates of unplanned surgical intervention (due to obstruction or perforation) have been reported. We examined a large national dataset to determine the rate of unplanned surgical intervention in these patients. METHODS: Surveillance Epidemiology and End Results-Medicare were queried for patients with metastatic colorectal cancer receiving chemotherapy (1998-2013). Patient who underwent planned surgery to the primary or metastasectomy were excluded. The primary outcome was the need for nonelective surgery. Time to surgery or death was measured. Conditional analyses were performed to determine the risk of surgical intervention at 6-month, 1-, and 2-year after diagnosis. RESULTS: The analytic cohort consisted of 4692 patients (median age = 75). At 24 months, 80% of the patients had died. The overall unplanned intervention rate was 12%. The probability of requiring unplanned surgery between 6 and 12 months was 8.1%; 12 and 24 months = 6.7%, and >24 months = 5.3%. Males, those with right-sided tumors, and older patients were less likely to require surgery. CONCLUSIONS: Patients treated with palliative chemotherapy who are not resected upfront are unlikely to require unplanned surgery. Prophylactic surgery to reduce the risk of perforation or obstruction may not be necessary.

A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer.

BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA-damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects. METHODS: A single-arm, open-label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies. Fifty patients received temozolomide (150 mg/m2 /d) on days 1 to 5 and veliparib (40 mg twice daily) on days 1 to 7 of each 28-day cycle. Another 5 patients with mismatch repair-deficient (dMMR) tumors were also enrolled. Twenty additional patients were then treated with temozolomide at 200 mg/m2 /d. Archived tumor specimens were used for immunohistochemistry to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression levels. RESULTS: The combination was well tolerated, although some patients required dose reductions for myelosuppression. The primary endpoint was successfully met with a DCR of 24% and 2 confirmed partial responses. The median progression-free survival was 1.8 months, and the median overall survival was 6.6 months. PTEN protein expression and MGMT protein expression were not predictors of DCR. There was also a suggestion of worse outcomes for patients with dMMR tumors. CONCLUSIONS: In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m2 /d, and it was clinically active. PARP inhibitor-based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337-46. © 2018 American Cancer Society.

Immuno-Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PD-L1 Testing May Not Be Enough.

PURPOSE: The treatment of patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas has been transformed by the U.S. Food and Drug Administration approval of pembrolizumab. Tumor and adjacent tissue must stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. However, some patients with PD-L1-negative tumors also benefit from pembrolizumab. High microsatellite instability (MSI) and tumor mutational load (TML) are positive predictive biomarkers for immune checkpoint inhibition (ICI) in other tumors. We sought to identify more patients who could benefit from ICI using alternative PD-L1 thresholds, MSI, and TML. METHODS: Tumor specimens underwent next-generation sequencing (NGS) and PD-L1 testing using immunohistochemistry. NGS was used to determine TML and MSI. RESULTS: We profiled 581 G/GEJ adenocarcinoma specimens. PD-L1 staining was scored for intensity (0, none; 1+, weak; 2+, moderate; 3+, strong). Using 2+ staining at a 5% threshold, 9.3% of tumors were PD-L1 positive, and using 1+ staining at 1%, 16.2% were PD-L1 positive. 6.9% of tumors had high MSI. High TML (≥17 mutations per megabase) was seen in 6.9%, and medium TML (≥7) was seen in 56.5% of tumors. Thirty (5.2%) PD-L1-negative tumors at the 1+, 1% threshold had high TML or high MSI. Primary tumors had higher rates of high TML (8.8% vs. 3.9%; p = .0377) and high MSI (8.5% vs. 3.9%; p = .0471) than metastases. CONCLUSION: PD-L1 testing alone fails to detect patients who may benefit from ICI. Lower PD-L1 thresholds and TML testing should be considered in future clinical trials. IMPLICATIONS FOR PRACTICE: Pembrolizumab is approved by the U.S. Food and Drug Administration for patients with refractory gastric and gastroesophageal cancers if the tumor and adjacent tissue stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. Tumor mutational load, microsatellite instability (MSI), and alternative PD-L1 testing thresholds may serve as predictive biomarkers for response to immune checkpoint inhibition, and standard PD-L1 testing will not identify all patients who may benefit from this therapy.

Molecular Testing to Optimize and Personalize Decision Making in the Management of Colorectal Cancer.

Recent improvements in our understanding of the biology of colorectal cancer have led to the identification of several important prognostic and predictive markers of disease-associated risk and treatment response for the individual patient. Proper utilization of these biomarkers can enable physicians to tailor therapeutic strategies to maximize the likelihood of response and minimize treatment toxicity. In the management of colorectal cancer, tremendous progress has been made in the development of strategies for immune checkpoint inhibition; in refinement of agents and approaches used in targeted therapy; and in techniques for molecular subtyping of tumor samples that have identified patient subgroups with clinically relevant cellular differences potentially affecting clinical management and treatment outcome. In this article, we discuss several of the commonly tested markers in colorectal cancer-including microsatellite instability, RAS/RAF, DPD, HER2, UTG1A1, TS, and Immunoscore-and highlight their prevalence, prognostic and predictive value, and current role in the overall treatment paradigm.

The challenge of measuring intra-individual change in fatigue during cancer treatment.

PURPOSE: To evaluate how well three different patient-reported outcomes (PROs) measure individual change. METHODS: Two hundred and fourteen patients (from two sites) initiating first or new chemotherapy for any stage of breast or gastrointestinal cancer participated. The 13-item FACIT Fatigue scale, a 7-item PROMIS® Fatigue Short Form (PROMIS 7a), and the PROMIS® Fatigue computer adaptive test (CAT) were administered monthly online for 6 months. Reliability of measured change was defined, under a population mixed effects model, as the ratio of estimated systematic variance in rate of change to the estimated total variance of measured individual differences in rate of change. Precision of individual measured change, the standard error of measurement of change, was given by the square root of the rate-of-change sampling variance. Linear and quadratic models were examined up to 3 and up to 6 months. RESULTS: A linear model for measured change showed the following by 6 and 3 months, respectively: PROMIS CAT (0.363 and 0.342); PROMIS SF (0.408 and 0.533); FACIT (0.459 and 0.473). Quadratic models offered no noteworthy improvement over linear models. Both reliability and precision results demonstrate the need to improve the measurement of intra-individual change. CONCLUSIONS: These results illustrate the challenge of reliably measuring individual change in fatigue with a level of confidence required for intervention. Optimizing clinically useful measurement of intra-individual differences over time continues to pose a challenge for PROs.

Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.

BACKGROUND: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. RESULTS: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. CONCLUSIONS: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.

Addressing barriers to increased adoption of DPYD genotyping at a large multisite cancer center.

PURPOSE: To describe the implementation of an in-house genotyping program to detect genetic variants linked to impaired dihydropyrimidine dehydrogenase (DPD) metabolism at a large multisite cancer center, including barriers to implementation and mechanisms to overcome barriers to facilitate test adoption. SUMMARY: Fluoropyrimidines, including fluorouracil and capecitabine, are commonly used chemotherapy agents in the treatment of solid tumors, such as gastrointestinal cancers. DPD is encoded by the DPYD gene, and individuals classified as DPYD intermediate and poor metabolizers due to certain genetic variations in DPYD can experience reduced fluoropyrimidine clearance and an increased risk of fluoropyrimidine-related adverse events. Although pharmacogenomic guidelines provide evidence-based recommendations for DPYD genotype-guided dosing, testing has not been widely adopted in the United States for numerous reasons, including limited education/awareness of clinical utility, lack of testing recommendations by oncology professional organizations, testing cost, lack of accessibility to a comprehensive in-house test and service, and prolonged test turnaround time. Based on stakeholder feedback regarding barriers to testing, we developed an in-house DPYD test and workflow to facilitate testing in multiple clinic locations at Levine Cancer Institute. Across 2 gastrointestinal oncology clinics from March 2020 through June 2022, 137 patients were genotyped, and 13 (9.5%) of those patients were heterozygous for a variant and identified as DPYD intermediate metabolizers. CONCLUSION: Implementation of DPYD genotyping at a multisite cancer center was feasible due to operationalization of workflows to overcome traditional barriers to testing and engagement from all stakeholders, including physicians, pharmacists, nurses, and laboratory personnel. Future directions to scale and sustain testing in all patients receiving a fluoropyrimidine across all Levine Cancer Institute locations include electronic medical record integration (eg, interruptive alerts), establishment of a billing infrastructure, and further refinement of workflows to improve the rate of pretreatment testing.

COVID-19 vaccine uptake trends in SARS-CoV-2 previously infected cancer patients.

Purpose: Cancer patients are at high risk of developing severe illness from SARS-CoV-2 infection, but risk is lowered with receipt of COVID-19 vaccine. COVID-19 vaccination uptake among previously infected cancer patients may be influenced by an assumption of natural immunity, predicted weak immune response, or concerns about vaccine safety. The objective of this study was to evaluate COVID-19 vaccine uptake trends in cancer patients previously infected with SARS-CoV-2. Materials and Methods: Medical records of 579 sequential cancer patients undergoing active treatment at Levine Cancer Institute who tested positive for COVID-19 between January 2020 and January 2021 were evaluated. Patients who died prior to vaccine eligibility were excluded from the analysis. Demographic, clinical, and COVID-19 related characteristics were analyzed to identify prognostic factors for COVID-19 vaccine uptake as this information could be important for health policy design for future pandemics. Results: Eighty-one patients died prior to the availability of COVID-19 vaccines. The acceptance rate of COVID-19 vaccination among 498 previously infected cancer patients was 54.6%. Of the patients with known vaccination dates, 76.8% received their first vaccine by April 17th, 2021. As of November 30, 2021, 23.7.% of eligible patients were boosted. In univariate models, older age, female sex, higher income, solid tumor cancer type, and hormone therapy were significantly associated with higher vaccine uptake, while Hispanic/Latino ethnicity was significantly associated with lower vaccine uptake. In a multivariable model, age (OR 1.18, 95% CI 1.10-1.28; p < 0.001), female sex (OR 1.80, 95% CI 1.22-2.66; p = 0.003), and higher income (OR 1.11, 95% CI 1.01-1.22; p = 0.032), were predictive of COVID-19 vaccine uptake. Conclusions: Overall, vaccine uptake was low among our cohort of previously infected cancer patients. Older age, female sex, and higher income were the only variables associated with COVID-19 vaccine uptake within this vulnerable patient population.

A phase 1 study of efatutazone, an oral peroxisome proliferator-activated receptor gamma agonist, administered to patients with advanced malignancies.

BACKGROUND: Efatutazone (CS-7017), a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone. METHODS: Patients with advanced solid malignancies and no curative therapeutic options were enrolled to receive a given dose of efatutazone, administered orally (PO) twice daily for 6 weeks, in a 3 + 3 intercohort dose-escalation trial. After the third patient, patients with diabetes mellitus were excluded. Efatutazone dosing continued until disease progression or unacceptable toxicity, with measurement of efatutazone pharmacokinetics and plasma adiponectin levels. RESULTS: Thirty-one patients received efatutazone at doses ranging from 0.10 to 1.15 mg PO twice daily. Dose escalation stopped when maximal impact on PPARγ-related biomarkers had been reached before any protocol-defined maximum-tolerated dose level. On the basis of a population pharmacokinetic/pharmacodynamic analysis, the recommended phase 2 dose was 0.5 mg PO twice daily. A majority of patients experienced peripheral edema (53.3%), often requiring diuretics. Three episodes of dose-limiting toxicities, related to fluid retention, were noted in the 0.10-, 0.25-, and 1.15-mg cohorts. Of 31 treated patients, 27 were evaluable for response. A sustained partial response (PR; 690 days on therapy) was observed in a patient with myxoid liposarcoma. Ten additional patients had stable disease (SD) for ≥60 days. Exposures were approximately dose proportional, and adiponectin levels increased after 4 weeks of treatment at all dose levels. Immunohistochemistry of archived specimens demonstrated that PPARγ and retinoid X receptor expression levels were significantly greater in patients with SD for ≥60 days or PR (P = .0079), suggesting a predictive biomarker. CONCLUSIONS: Efatutazone demonstrates acceptable tolerability with evidence of disease control in patients with advanced malignancies.

Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors.

BACKGROUND: Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or ßIII-tubulin. MATERIALS AND METHODS: This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements. RESULTS: Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90-100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT. CONCLUSIONS: On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.

Impact of a Clinical Genomics Program on Trial Accrual for Targeted Treatments: Practical Approach Overcoming Barriers to Accrual for Underserved Patients.

PURPOSE: Clinical trials of novel and targeted agents increasingly require biomarkers for eligibility. Precision oncology continues to evolve, but challenges hamper broad use of molecular profiling (MP) that could increase the number of patients benefiting from targeted therapy. We implemented an integrated clinical genomics program (CGP), including a virtual Molecular Tumor Board (MTB), and examined its impact on MP use and impact on clinical trial accrual in a multisite regional-based cancer system with an emphasis on effects for isolated clinicians. METHODS: We assessed MP and MTB use from 2010 to 2020 by practice location, physician experience, and patient characteristics. Use of MTB-recommended treatments was assessed. Clinical trial enrollment was evaluated for patients with MP versus MP and MTB review. RESULTS: After CGP implementation, the number of physicians using MP and the number of MP tests increased ≥ 10-fold. The proportion of Hispanic patients with MP was the same as that in the system (both 2%) with marginal differences observed in the proportion of African Americans tested compared with the system population (16% v 19%). Physicians followed MTB treatment recommendations in 74% of cases. Rapid clinical decline was the most common reason why physicians did not follow MTB recommendations. Clinical trial accrual was 15% (669 of 4,459) for patients with MP alone and 28% (94 of 334) with both MP and MTB review. Clinical trial availability and patient out-of-pocket costs affected MP use. CONCLUSION: Integrating CGP into clinical workflow with decision support tools, trial matching, and management of patient costs led to increased use of MP by physicians with all levels of experience, enhanced clinical trial accrual, and has the potential to reduce disparities in MP.

Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers.

PURPOSE: Promising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking. MATERIALS AND METHODS: Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers. RESULTS: Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01). CONCLUSION: This study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.

Association of Homologous Recombination-DNA Damage Response Gene Mutations with Immune Biomarkers in Gastroesophageal Cancers.

The prevalence of homologous recombination-DNA damage response (HR-DDR) genetic alterations is of therapeutic interest in gastroesophageal cancers. This study is a comprehensive assessment of HR-DDR mutation prevalence across gastroesophageal adenocarcinomas and squamous cell carcinomas. Here we investigate the association of HR-DDR mutations with known predictors for immune-checkpoint inhibition [deficiency in mismatch-repair (dMMRP), tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1)]. We confirmed HR-DDR mutations are present in a subset of gastroesophageal adenocarcinomas (23%) and gastroesophageal squamous cell carcinomas (20%). Biomarker expression of dMMRP (18% vs. 1%) and TMB-high with a cutoff of ≥10 mt/MB (27% vs. 9%) was significantly more prevalent in the DDR-mutated cohort compared with the non-DDR-mutated cohort. Mean combined positive score for PD-L1 in the total adenocarcinoma cohort was significantly higher in the DDR-mutated cohort compared with the non-DDR-mutated cohort (10.1 vs. 5.8). We demonstrated that alterations in ARID1A, BRCA2, PTEN, and ATM are correlated with dMMRP, TMB-high, and increased PD-L1 expression in gastroesophageal adenocarcinomas. Our findings show that a subset of gastroesophageal tumors harbor HR-DDR mutations correlated with established immune biomarkers. By better understanding the relationship between HR-DDR mutations and immune biomarkers, we may be able to develop better immunotherapy combination strategies to target these tumors.

Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma.

PURPOSE: KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments. EXPERIMENTAL DESIGN: Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination. RESULTS: Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin. CONCLUSIONS: KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.

Molecular characteristics and clinical outcomes of patients with Neurofibromin 1-altered metastatic colorectal cancer.

Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings.