Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations.

Biliary tract cancers (BTC) are a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC. In this review, we assess the neoadjuvant and adjuvant clinical trials for the treatment of BTC and discuss the challenges and limitations of clinical trials, as well as future directions for the treatment of BTC.

A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle. Between January 15, 2016 and October 24, 2018, 104 pts were randomized at four international sites, with 96 pts undergoing treatment, 62 in Arm A and 34 in Arm B. Median overall survival was 7.15 months for Arm A and 7.66 months for Arm B (HR 0.93, 95% CI: 0.58-1.47, P = .75). The Kaplan-Meier rates of progression free survival at 4 months were 32% in Arm A and 26% in Arm B. Common ≥Grade 3 treatment related adverse events in Arm A were neutropenia (42%), anemia (18%), diarrhea (11%), compared to Arm B pts with neutropenia (12%), anemia (12%). Guadecitabine and irinotecan had similar OS compared to standard of care TAS-102 or regorafenib, with evidence of target modulation. Clinical trial information: NCT01896856.

Temporal Changes in Cholangiocarcinoma Incidence and Mortality in the United States from 2001 to 2017.

BACKGROUND: Previous studies report increasing cholangiocarcinoma (CCA) incidence up to 2015. This contemporary retrospective analysis of CCA incidence and mortality in the US from 2001-2017 assessed whether CCA incidence continued to increase beyond 2015. PATIENTS AND METHODS: Patients (≥18 years) with CCA were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results 18 cancer registry (International Classification of Disease for Oncology [ICD-O]-3 codes: intrahepatic [iCCA], C221; extrahepatic [eCCA], C240, C241, C249). Cancer of unknown primary (CUP) cases were identified (ICD-O-3: C809; 8140/2, 8140/3, 8141/3, 8143/3, 8147/3) because of potential misclassification as iCCA. RESULTS: Forty-thousand-and-thirty CCA cases (iCCA, n=13,174; eCCA, n=26,821; iCCA and eCCA, n=35) and 32,980 CUP cases were analyzed. From 2001-2017, CCA, iCCA, and eCCA incidence (per 100 000 person-years) increased 43.8% (3.08 to 4.43), 148.8% (0.80 to 1.99), and 7.5% (2.28 to 2.45), respectively. In contrast, CUP incidence decreased 54.4% (4.65 to 2.12). CCA incidence increased with age, with greatest increase among younger patients (18-44 years, 81.0%). Median overall survival from diagnosis was 8, 6, 9, and 2 months for CCA, iCCA, eCCA, and CUP. From 2001-2016, annual mortality rate declined for iCCA (57.1% to 41.2%) and generally remained stable for eCCA (40.9% to 37.0%) and for CUP (64.3% to 68.6%). CONCLUSIONS: CCA incidence continued to increase from 2001-2017, with greater increase in iCCA versus eCCA, whereas CUP incidence decreased. The divergent CUP versus iCCA incidence trends, with overall greater absolute change in iCCA incidence, provide evidence for a true increase in iCCA incidence that may not be wholly attributable to CUP reclassification.

Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study.

BACKGROUND: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway. METHODS: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing. FINDINGS: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths. INTERPRETATION: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population. FUNDING: F Hoffmann-La Roche-Genentech.

Development, Practice Patterns, and Early Clinical Outcomes of a Multidisciplinary Liver Cancer Clinic.

Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.

Current and emerging therapies for patients with advanced pancreatic ductal adenocarcinoma: a bright future.

Pancreatic ductal adenocarcinoma is the seventh leading cause of cancer death worldwide with an estimated 432 242 deaths occurring in 2018. This estimate, in conjunction with the findings that pancreatic ductal adenocarcinoma incidence is rising and that pancreatic ductal adenocarcinoma has the highest case-fatality rate of any solid tumour, highlights the urgency for designing novel therapeutic strategies to combat this deadly disease. Through the efforts of the global research community, our knowledge of the factors that lead to the development of pancreatic ductal adenocarcinoma, its progression, and the interplay between tumour cells and their surrounding microenvironment have improved substantially. Although these scientific advances have not yet translated into targeted or immunotherapy strategies that are effective for most patients with pancreatic ductal adenocarcinoma, important incremental progress has been made particularly for the treatment of specific molecular subgroups of tumours. Although PD-1 inhibitors for mismatch-repair-deficient tumours and NTRK inhibitors for tumours containing NTRK gene fusions are the most recent targeted agents approved by the US Food and Drug Administration, olaparib for germline BRCA-mutated pancreatic ductal adenocarcinoma is expected to be approved soon in the maintenance setting. These recent advances show the accelerated pace at which pancreatic ductal adenocarcinoma drugs are achieving successful clinical outcomes. Here we review the current understanding of the pathophysiology of pancreatic ductal adenocarcinoma, recent advances in the understanding of the stromal microenvironment, current standard-of-care treatment, and novel therapeutic targets and strategies that hold promise for improving patient outcomes. We predict that there will be major breakthroughs in the treatment of pancreatic ductal adenocarcinoma in the next 5-10 years. These breakthroughs will result from the increased understanding of the treatment barriers imposed by the tumour-associated stroma, and from the development of novel approaches to re-engineer the tumour microenvironment in favour of effective anticancer responses.

Spirituality in cancer patients on phase 1 clinical trials.

OBJECTIVES: Patients with cancer who are at a transition to Phase I investigational treatments have been identified as an underserved population with regard to palliative care. This disease transition is often accompanied by spiritual and existential concerns. The study objective was to conduct a secondary analysis of data from a larger study testing a palliative care intervention. This paper reports the findings of this secondary focus on the spiritual needs of this population. METHODS: Patients (n = 479) were accrued to this study prior to initiating a Phase I clinical trial with data collected at baseline, and 4, 12, and 24 week follow-up. RESULTS: Qualitative data revealed that the transition to Phase 1 trial participation is a time of balancing hope for extended life with the reality of advancing disease. Quantitative results demonstrated increased spirituality over time in both religious- and non-religious-affiliated patients. CONCLUSIONS: Patients entering Phase I trials have important spiritual needs as they face treatment decisions, advancing disease, and often mortality. Spiritual care should be provided to seriously ill patients as a component of quality care.

Cost-utility of colorectal cancer screening at 40 years old for average-risk patients.

The incidence of colorectal cancer (CRC) is increasing in patients under the age of 50. The purpose of this study was to assess the cost-utility of available screening modalities starting at 40 years in the general population compared to standard screening at 50 years old. A decision tree modeling average-risk of CRC in the United States population was constructed for the cost per quality-adjusted life year (QALY) of the five most common and effective CRC screening modalities in average-risk 40-year olds versus deferring screening until 50 years old (standard of care) under a limited societal perspective. All parameters were derived from existing literature. We evaluated the incremental cost-utility ratio of each comparator at a willingness-to-pay threshold of $50,000/QALY and included multivariable probabilistic sensitivity analysis. All screening modalities assessed were more cost-effective with increased QALYs than current standard care (no screening until 50). The most favorable intervention by net monetary benefit was flexible sigmoidoscopy ($3284 per person). Flexible sigmoidoscopy, FOBT, and FIT all dominated the current standard of care. Colonoscopy and FIT-DNA were both cost-effective (respectively, $4777 and $11,532 per QALY). The cost-effective favorability of flexible sigmoidoscopy diminished relative to colonoscopy with increasing willingness-to-pay. Regardless of screening modality, CRC screening at 40 years old is cost-effective with increased QALYs compared to current screening initiation at 50 years old, with flexible sigmoidoscopy most preferred. Consideration should be given for a general recommendation to start screening at age 40 for average risk individuals.

Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer.

Overexpression and cellular mis-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death. Our preclinical data showed cooperative activity with the AURKA inhibitor alisertib and platinum agents in cell lines and xenografts, and suggested an optimal treatment window. Therefore, this study was designed to determine the maximum-tolerated dose (MTD) of alisertib in combination with modified FOLFOX (mFOLFOX), as this is a standard platinum-based therapy for gastrointestinal cancers. Standard 3 + 3 dose escalation was used, where the starting dose of alisertib was 10 mg twice daily (Days 1-3), with leucovorin (400 mg/m2) and oxaliplatin (85 mg/m2) on Day 2 followed by continuous 46-h 5-FU (2400 mg/m2) infusion on Days 2-4 in 14-day cycles. Fourteen patients with advanced gastrointestinal cancers were enrolled and two doses explored; two patients were not evaluable for dose-limiting toxicity (DLT) and replaced. Two patients experienced DLTs at 20 mg of alisertib (Grade 3 fatigue (n = 2); Grade 3 nausea, vomiting, dehydration with hospitalization (n = 1)). MTD was 10 mg alisertib with 85 mg/m2 oxaliplatin and 2400 mg/m2 5-FU. Most frequent toxicities were nausea (57%), diarrhea, fatigue, neuropathy, and vomiting (43%), and anorexia and anemia (36%); most were Grade 1-2. One patient with colorectal cancer had a partial response of 12 evaluable patients, and four patients had stable disease. Alisertib in combination with mFOLFOX did not demonstrate unexpected side effects, but the regimen was only tolerable at the lowest dose investigated.

Readmission Adversely Affects Survival in Surgical Rectal Cancer Patients.

BACKGROUND: Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS: Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS: Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS: Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

Correction to: Phase I study combining the aurora kinase a inhibitor alisertib with mFOLFOX in gastrointestinal cancer.

The authors would like to note that the investigator affiliations have been corrected to reflect the actual affiliations of each author. The authors would also like to note an amendment to the first name of the second author. Nilo Azad was changed to reflect the full name of the author, which is Nilofer S. Azad as shown above. The original article has been corrected.

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma. METHODS: In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR). RESULTS: A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension. CONCLUSIONS: Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

Academic Cancer Center Phase I Program Development.

Multiple factors critical to the effectiveness of academic phase I cancer programs were assessed among 16 academic centers in the U.S. Successful cancer centers were defined as having broad phase I and I/II clinical trial portfolios, multiple investigator-initiated studies, and correlative science. The most significant elements were institutional philanthropic support, experienced clinical research managers, robust institutional basic research, institutional administrative efforts to reduce bureaucratic regulatory delays, phase I navigators to inform patients and physicians of new studies, and a large cancer center patient base. New programs may benefit from a separate stand-alone operation, but mature phase I programs work well when many of the activities are transferred to disease-oriented teams. The metrics may be useful as a rubric for new and established academic phase I programs. The Oncologist 2017;22:369-374.

A final report of a phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy (LDFWAR) in patients with advanced solid malignancies and peritoneal carcinomatosis with a dose escalation in ovarian and fallopian tube cancers.

BACKGROUND: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). METHODS: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed. RESULTS: 32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. CONCLUSION: ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.

A robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of 5-azacytidine.

The DNA methyltransferase inhibitor 5-azacytidine is being evaluated clinically as an oral formulation to treat various solid tumors. A sensitive, reliable method was developed to quantitate 5-azacytidine using LC-MS/MS to perform detailed pharmacokinetic studies. The drug of interest was extracted from plasma using Oasis MCX ion exchange solid-phase extraction 96-well plates. Chromatographic separation was achieved with a YMC J'sphere M80 C18 column and isocratic elution with a methanol-water-formic acid (15:85:0.1, v/v/v) mobile phase over a 7 min total analytical run time. An AB Sciex 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of 5-azacytidine. The assay range was 5-500 ng/mL and proved to be accurate (97.8-109.1%) and precise (CV ≤ 9.8%). Tetrahydrouridine was used to stabilize 5-azacytidine in blood/plasma samples. With the addition of tetrahydrouridine, long-term frozen plasma stability for 5-azacytidine at -70°C has been determined for at least 323 days. The method was applied for the measurement of total plasma concentrations of 5-azacytidine in a cancer patient receiving a 300 mg oral daily dose.

Performance characteristics of next-generation sequencing in clinical mutation detection of colorectal cancers.

Activating mutations in downstream genes of the epidermal growth factor receptor (EGFR) pathway may cause anti-EGFR resistance in patients with colorectal cancers. We present performance characteristics of a next-generation sequencing assay designed to detect such mutations. In this retrospective quality assessment study, we analyzed mutation detected in the KRAS, NRAS, BRAF, and PIK3CA genes by a clinically validated next-generation sequencing assay in 310 colorectal cancer specimens. Tumor cellularity and mutant allele frequency were analyzed to identify tumor heterogeneity and mutant allele-specific imbalance. Next-generation sequencing showed precise measurement of mutant allele frequencies and detected 23% of mutations with 2-20% mutant allele frequencies. Of the KRAS mutations detected, 17% were outside of codons 12 and 13. Among PIK3CA mutations, 48% were outside of codons 542, 545, and 1047. The percentage of tumors with predicted resistance to anti-EGFR therapy increased from 40% when testing for only mutations in KRAS exon 2 to 47% when testing for KRAS exons 2-4, 48% when testing for KRAS and NRAS exons 2-4, 58% when including BRAF codon 600 mutations, and 59% when adding PIK3CA exon 20 mutations. Right-sided colorectal cancers carried a higher risk of predicted anti-EGFR resistance. A concomitant KRAS mutation was detected in 51% of PIK3CA, 23% of NRAS, and 33% of kinase-impaired BRAF-mutated tumors. Lower than expected mutant allele frequency indicated tumor heterogeneity, while higher than expected mutant allele frequency indicated mutant allele-specific imbalance. Two paired neuroendocrine carcinomas and adjacent adenomas showed identical KRAS mutations, but only PIK3CA mutations in neuroendocrine carcinomas. Next-generation sequencing is a robust tool for mutation detection in clinical laboratories. It demonstrates high analytic sensitivity and broad reportable range, and it provides simultaneous detection of concomitant mutations and a quantitative measurement of mutant allele frequencies to predict tumor heterogeneity and mutant allele-specific imbalance.

CHFR silencing or microsatellite instability is associated with increased antitumor activity of docetaxel or gemcitabine in colorectal cancer.

Phenotypic differences among cancers with the same origin may be associated with chemotherapy response. CHFR silencing associated with DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumor types. However, the use of microsatellite instability (MSI:unstable-MSS:stable) as a predictive marker for therapeutic effect has had conflicting results. We examined these molecular alterations as predictors of chemotherapy sensitivity in colorectal cancer (CRC). Differential sensitivity to docetaxel and gemcitabine was compared to potential predictive biomarkers CHFR methylation and MSI status. Cell lines that were MSI-H/CHFR-methylated, MSS/CHFR-methylated and MSS/CHFR-unmethylated were assessed for in vivo sensitivity of CRC cell line xenografts to docetaxel and/or gemcitabine. We observed increased sensitivity in vitro to gemcitabine in cell lines with MSI and docetaxel in cell lines with CHFR inactivation via DNA methylation. In vivo treatment of human xenografts confirmed differential sensitivity, with the MSI-H/CHFR-methylated line RKO having tumor growth inhibition to each agent, and at least additive tumor growth inhibition with combination therapy. The MSS-CHFR-unmethylated line, CACO2 , was resistant to single and combination therapy, while COLO205, the MSS/CHFR-methylated line, showed tumor growth inhibition with docetaxel, but not gemcitabine, therapy. CHFR methylation in CRC cell lines predicted for sensitivity in vitro and in vivo to docetaxel, while MSI-H cell lines were more sensitive to gemcitabine. These data suggest that a subset of CRC patients would be selectively sensitive to a novel combination of gemcitabine and docetaxel, and are the basis for an ongoing clinical trial of this combination in a biomarker-selected patient population.

A randomized pilot trial of a telephone-based couples intervention for physical intimacy and sexual concerns in colorectal cancer.

BACKGROUND: We previously developed and piloted a telephone-based intimacy enhancement (IE) intervention addressing sexual concerns of colorectal cancer patients and their partners in an uncontrolled study. The current study tested the feasibility, acceptability, and preliminary efficacy of the IE intervention in a randomized, controlled trial. METHODS: Twenty-three couples were randomized to either the four-session IE condition or to a wait list control condition and completed sexual and relationship outcomes measures. The IE intervention teaches skills for coping with sexual concerns and improving intimacy. Feasibility and acceptability were assessed through enrollment and post-treatment program evaluations, respectively. Effect sizes were calculated by comparing differences in average pre/post change scores across completers in the two groups (n = 18 couples). RESULTS: Recruitment and attrition data supported feasibility. Program evaluations for process (e.g., ease of participation) and content (e.g., relevance) demonstrated acceptability. Engaging in intimacy-building activities and communication were the skills rated as most commonly practiced and most helpful. For patients, positive effects of the IE intervention were found for female and male sexual function, medical impact on sexual function, and self-efficacy for enjoying intimacy (≥.58); no effects were found on sexual distress or intimacy and small negative effects for sexual communication, and two self-efficacy items. For partners, positive IE effects were found for all outcomes; the largest were for sexual distress (.69), male sexual function (1.76), communication (.97), and two self-efficacy items (≥.87). CONCLUSIONS: The telephone-based IE intervention shows promise for couples facing colorectal cancer. Larger multi-site intervention studies are necessary to replicate findings.