Do resected colorectal cancer patients need early chest imaging? Impact of clinicopathologic characteristics on time to development of pulmonary metastases.

BACKGROUND AND OBJECTIVES: For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. METHODS: We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. RESULTS: Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. CONCLUSIONS: We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.

SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC.

Patients with both BRAF V600E mutations and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) have poor prognosis. Currently, there are no specifically targeted first-line treatment options indicated for patients with mCRC whose tumors harbor both molecular aberrations. Pembrolizumab is a checkpoint inhibitor approved for the treatment of MSI-H/dMMR mCRC, and the BRAF inhibitor encorafenib, in combination with cetuximab, is approved for previously treated BRAF V600E-mutant mCRC. Combination of pembrolizumab with encorafenib and cetuximab may synergistically enhance antitumor activity in patients with BRAF V600E-mutant, MSI-H/dMMR mCRC. SEAMARK is a randomized phase II study comparing the efficacy of the combination of pembrolizumab with encorafenib and cetuximab versus pembrolizumab alone in patients with previously untreated BRAF V600E-mutant, MSI-H/dMMR mCRC.

Colorectal cancer (CRC) occurs when there is an abnormal growth of cells (known as a tumor) in the colon or rectum. Some people with CRC have changes in their tumor genes (known as gene mutations). A gene is a piece of DNA that tells the cell to make specific molecules, such as proteins. Mutations in a gene called BRAF can turn on signals that help the cancer cells grow. Gene mutations that impair DNA repair mechanisms can also make the cancer cells grow more quickly and allow the immune system to detect the cancer cells as being foreign to the body. Targeted therapy is a type of cancer treatment that turns off specific genes and proteins involved in cancer cell survival and growth. BRAF and EGFR inhibitors are targeted therapies that work well together in treating people with BRAF-mutant CRC. BRAF proteins can help cancer cells grow, and BRAF inhibitors block these proteins to prevent, slow, or stop the growth of the cancer cells. Immunotherapy is a type of cancer treatment that helps a person's immune system fight cancer. Immunotherapy is effective for treating CRC that has mutations in the DNA repair mechanisms. By combining targeted therapy and immunotherapy, patients may be able to live longer without their disease getting worse. In the SEAMARK study, we will use a treatment combination including a BRAF inhibitor (encorafenib), an EGFR inhibitor (cetuximab) and an immunotherapy (pembrolizumab) in patients with CRC who have a BRAF mutation and deficiencies in the DNA repair mechanism. Clinical Trial Registration: NCT05217446 (ClinicalTrials.gov), 2021-003715-26 (EudraCT).

Institution-Wide Retreats Foster Organizational Learning and Action at a Comprehensive Cancer Center.

Providing safe and informed healthcare for sexual and gender minority (SGM) individuals with cancer is stymied by the lack of sexual orientation and gender identity (SOGI) data reliably available in health records and by insufficient training for staff. Approaches that support institutional learning, especially around sensitive topics, are essential for hospitals seeking to improve practices impacting patient safety and research. We engineered annual institutional retreats to identify and unify stakeholders, promote awareness of gaps and needs, identify initiatives, minimize redundant projects, and coordinate efforts that promote improvements in SGM cancer care, education, and research. The 2022 and 2023 retreats employed a 4-h hybrid format allowing virtual and in-person engagement. Retreat organizers facilitated small-group discussions for brainstorming among participants. We performed descriptive statistics from retreat evaluations. The retreats engaged 104 attendees from distinct departments and roles. Participants expressed robust satisfaction, commending the retreat organization and content quality. Notably, the first retreat yielded leadership endorsement and funding for a Quality Improvement pilot to standardize SOGI data collection and clinical staff training. The second retreat provided a platform for updates on focused efforts across the institution and for receiving direction regarding national best practices for SGM care and research. We report the processes and outcomes of institution-wide retreats, which served as a platform for identifying gaps in organizational healthcare practices and research for SGM individuals with cancer. The strategies described herein may be readily scaled at other cancer hospitals seeking to learn and enact system-wide practice changes that support the needs of SGM patients and families.

Use of Circulating Cell-Free DNA to Guide Precision Medicine in Patients with Colorectal Cancer.

Patient-specific biomarkers form the foundation of precision medicine strategies. To realize the promise of precision medicine in patients with colorectal cancer (CRC), access to cost-effective, convenient, and safe assays is critical. Improvements in diagnostic technology have enabled ultrasensitive and specific assays to identify cell-free DNA (cfDNA) from a routine blood draw. Clinicians are already employing these minimally invasive assays to identify drivers of therapeutic resistance and measure genomic heterogeneity, particularly when tumor tissue is difficult to access or serial sampling is necessary. As cfDNA diagnostic technology continues to improve, more innovative applications are anticipated. In this review, we focus on four clinical applications for cfDNA analysis in the management of CRC: detecting minimal residual disease, monitoring treatment response in the metastatic setting, identifying drivers of treatment sensitivity and resistance, and guiding therapeutic strategies to overcome resistance.

Prospective Study of Perioperative Circulating Tumor DNA Dynamics in Patients Undergoing Hepatectomy for Colorectal Liver Metastases.

OBJECTIVE: To evaluate the association of perioperative ctDNA dynamics on outcomes after hepatectomy for CLM. SUMMARY BACKGROUND DATA: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established. METHODS: Patients underwent curative-intent hepatectomy after preoperative chemotherapy for CLM (2013-2017) with paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55 months. RESULTS: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but not after surgery (ctDNA+/-) in 19 (40%), and not at all (ctDNA-/-) in 11 (23%). Adverse tissue somatic mutations were detected in TP53 (n = 26; 54%), RAS (n = 23; 48%), SMAD4 (n = 5; 10%), FBXW7 (n = 3; 6%), and BRAF (n = 2; 4%). ctDNA+/+ was associated with worse RFS (median: ctDNA+/+, 6.0 months; ctDNA+/-, not reached; ctDNA-/-, 33.0 months; P = 0.001). Compared to ctDNA+/+, ctDNA+/- was associated with improved RFS [hazard ratio (HR) 0.24 (95% confidence interval (CI) 0.1-0.58)] and overall survival [HR 0.24 (95% CI 0.08-0.74)]. Adverse somatic mutations were not associated with survival. After adjustment for prehepatectomy chemotherapy, synchronous disease, and ≥2 CLM, ctDNA+/- and ctDNA-/- were independently associated with improved RFS compared to ctDNA+/+ (ctDNA+/-: HR 0.21, 95% CI 0.08-0.53; ctDNA-/-: HR 0.21, 95% CI 0.08-0.56). CONCLUSIONS: Perioperative ctDNA dynamics are associated with survival, identify patients with high recurrence risk, and may be used to guide treatment decisions and surveillance after hepatectomy for patients with CLM.

Phase II Trial of MEDI0457 and Durvalumab for Patients With Recurrent/Metastatic Human Papillomavirus-Associated Cancers.

BACKGROUND: Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. METHODS: Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p < 0.15; Ha: p ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. RESULTS: Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. CONCLUSIONS: The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate.

Prognostic and Predictive Markers for Patients With Anal Cancer.

Squamous cell carcinoma of the anus and anal canal is a rare malignancy with an increasing incidence in the United States. In the past 2 decades, the proportion of Americans diagnosed with incurable, metastatic anal cancer at the time of initial presentation has increased. Most cases are linked to prior infection with HPV. Although concurrent chemoradiotherapy has been the accepted standard treatment for patients with localized anal cancer over the past half century, therapeutic advances have increased options for patients with unresectable or incurable anal cancer over the past 5 years. Specifically, combination chemotherapy and immunotherapy with anti-PD-(L)1 antibodies has demonstrated efficacy in this setting. Greater understanding of molecular drivers of this viral-associated malignancy has provided critical insight into evolving biomarkers for the clinical management of anal cancer. The pervasiveness of HPV across cases of anal cancer has been leveraged for the development of HPV-specific circulating tumor DNA assays as a sensitive biomarker for prognosticating recurrence in patients with localized anal cancer who complete chemoradiation. For patients with metastatic disease, somatic mutations, well-characterized for anal cancer, have not shown utility in identifying patients who benefit from systemic treatments. Although the overall response rate to immune checkpoint blockade therapies is low for metastatic anal cancer, high immune activation within the tumor and PD-L1 expression may identify patients more likely to experience response. These biomarkers should be incorporated into the design of future clinical trials to personalize further treatment approaches in the evolving management of anal cancer.

Antibiotic Exposure Does Not Impact Immune Checkpoint Blockade Response in MSI-H/dMMR Metastatic Colorectal Cancer: A Single-Center Experience.

BACKGROUND: Immune checkpoint blockade (ICB) has improved outcomes for patients with microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) tumors. However, not all MSI-H/dMMR patients will exhibit the same ICB efficacy. Previous studies suggest that concomitant antibiotic use while receiving ICB may result in poorer outcomes. We aimed to evaluate this association in patients with MSI-H/dMMR metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A single-site, retrospective review of 57 patients with MSI-H/dMMR mCRC that received ICB was completed. Data collected included patient demographics, ICB information, and antibiotic use. Antibiotic exposure was considered from 90 days prior to ICB through 6 weeks after initiation. Primary endpoint was overall response rate (ORR). RESULTS: The majority of patients received pembrolizumab (27 [47%]) or nivolumab (17 [30%]) monotherapy as their ICB agent. Of the 57 patients, 19 (33.3%) had antibiotic exposure from 90 days prior to ICB initiation through 6 weeks after initiation with most (13 [68%]) having antibiotic use in the 30 days preceding ICB initiation. Similar ORRs were seen in both groups (P-value > .99). No difference was observed in OS (P-value .29) or PFS (P-value .36) between groups. CONCLUSION: Our data show no association of lower response rates or survival in those MSI-H/dMMR patients with mCRC who receive antibiotics around the initiation of ICB. This information needs to be confirmed in a larger prospective cohort.

Definitive Intensity-Modulated Chemoradiation for Anal Squamous Cell Carcinoma: Outcomes and Toxicity of 428 Patients Treated at a Single Institution.

BACKGROUND: Although intensity-modulated radiation therapy (IMRT) is considered the standard of care for the treatment of squamous cell carcinoma of the anus (SCCA), few large series have reported oncologic outcomes and toxicities. In this retrospective report, we aim to describe outcomes and toxicities after IMRT-based chemoradiation (CRT) for the treatment of SCCA, evaluate the impact of dose escalation (>54 Gy), and compare concurrent fluoropyrimidine in combination with either mitomycin or with cisplatin as chemosensitizers. METHODS: Patients treated at The University of Texas MD Anderson Cancer Center between January 1, 2003 and December 31, 2018 with IMRT-based CRT were included. Median time to locoregional recurrence, time to colostomy, and overall survival were estimated using the Kaplan-Meier method. RESULTS: A total of 428 patients were included; median follow-up was 4.4 years. Three hundred and thirty-four patients (78.0%) were treated with concurrent cisplatin and fluoropyrimidine, and 160 (37.4%) with >54 Gy. Two- and 5-year freedom from locoregional failure, freedom from colostomy failure, and overall survival were 86.5% and 81.2%, respectively, 90.0% and 88.3%, respectively, and 93.6% and 85.8%, respectively. Neither dose escalation nor mitomycin-based concurrent chemotherapy resulted in improved outcomes. Mitomycin-based concurrent chemotherapy was associated with in approximately 2.5 times increased grade 3 or greater acute toxicity. Radiation dose >54 Gy was associated with approximately 2.6 times increased Grade 3 or greater chronic toxicity. CONCLUSIONS: Our results suggest IMRT-based CRT with concurrent fluoropyrimidine and cisplatin is a safe and feasible option for patient with SCCA and may cause less acute toxicity. The role for radiation dose escalation is unclear and requires further study.

Phase I Study of Ramucirumab Plus Merestinib in Previously Treated Metastatic Colorectal Cancer: Safety, Preliminary Efficacy, and Pharmacokinetic Findings.

LESSONS LEARNED: The combination of the antivascular endothelial growth factor receptor 2 monoclonal antibody, ramucirumab, and the type II MET kinase inhibitor, merestinib, is tolerable. Preliminary efficacy data suggest that the combination may provide clinical benefit to patients with metastatic colorectal cancer (mCRC). Further development of this combination would likely necessitate the identification of subsets of patients with mCRC where the clinical benefit is of clinical relevance. BACKGROUND: This study evaluated safety, preliminary efficacy, and pharmacokinetics of ramucirumab plus merestinib in patients with MCR previously treated with oxaliplatin and/or irinotecan. METHODS: Open-label phase Ia/b study comprising 3+3 dose-limiting toxicity (DLT) observation and expansion parts. Treatment was ramucirumab 8 mg/kg on days 1 and 15 and merestinib 80 mg once daily (QD; 28-day cycle). Primary objective was safety and tolerability. Secondary objectives were pharmacokinetics and preliminary antitumor activity. Exploratory objective was biomarker associations. RESULTS: Safety findings: DLT (proteinuria) of 7 phase Ia patients (the expansion part started at the initial recommended dose level); 16 patients (70%) with grade ≥3 treatment-emergent adverse events (TEAEs); 10 patients (43%) with grade ≥3 treatment-related TEAEs. The most common grade ≥3 treatment-related TEAEs were fatigue (4 patients [17%]) and increased blood alkaline phosphatase, diarrhea, and hypertension (2 patients each [9%]). One patient discontinued treatment because of cholestatic hepatitis. Geometric mean trough concentrations at cycle 1, day 15, were ramucirumab, 24.8 µg/mL; merestinib, 130 ng/mL. No complete or partial response was seen; 12 patients (52%) achieved stable disease. Median progression-free survival was 3.3 months (95% confidence interval [CI]: 1.6-4.4). Median overall survival was 8.9 months (95% CI: 3.5-12.7). There were no associations between genetic alterations and efficacy. CONCLUSION: Ramucirumab plus merestinib is tolerable and may have clinical benefit in biomarker-unselected, heavily pretreated patients with mCRC.

High mutational concordance between primary colorectal tumors and associated pulmonary metastases.

BACKGROUND AND OBJECTIVES: Precision medicine has altered the management of colorectal cancer (CRC). However, the concordance of mutational findings between primary CRC tumors and associated pulmonary metastases (PM) is not well-described. This study aims to determine the concordance of genomic profiles between primary CRC and PM. METHODS: Patients treated for colorectal PM at a single institution from 2000 to 2017 were identified. Mutational concordance was defined as either both wild-type or both mutant alleles in lung and colorectal lesion; genes with opposing mutational profiles were reported as discordant. RESULTS: Thirty-eight patients met inclusion criteria, among whom KRAS, BRAF, NRAS, MET, RET, and PIK3CA were examined for concordance. High concordance was demonstrated among all evaluated genes, ranging from 86% (KRAS) to 100% concordance (NRAS, RET, and MET). De novo KRAS mutations were detected in the PM of 4 from 35 (11%) patients, 3 of whom had previously received anti-epidermal growth factor receptor (EGFR) therapy. Evaluation of Cohen's κ statistic demonstrated moderate to perfect correlation among evaluated genes. CONCLUSIONS: Because high intertumoral genomic homogeneity exists, it may be reasonable to use primary CRC mutational profiles to guide prognostication and targeted therapy for PM. However, the possibility of de novo KRAS-mutant PM should be considered, particularly among patients previously treated with anti-EGFR therapy.

Clinical and molecular characterization of early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated clinical and molecular features to identify those features unique to early-onset CRC that differentiate these patients from patients 50 years old or older. METHODS: Baseline characteristics were evaluated according to the CRC onset age with 3 independent cohorts. A fourth cohort was used to describe the impact of age on the consensus molecular subtype (CMS) prevalence. RESULTS: This retrospective review of more than 36,000 patients with CRC showed that early-onset patients were more likely to have microsatellite instability (P = .038), synchronous metastatic disease (P = .009), primary tumors in the distal colon or rectum (P < .0001), and fewer BRAF V600 mutations (P < .001) in comparison with patients 50 years old or older. Patients aged 18 to 29 years had fewer adenomatous polyposis coli (APC) mutations (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.35-0.90; P = .015) and an increased prevalence of signet ring histology (OR, 4.89; 95% CI, 3.23-7.39; P < .0001) in comparison with other patients younger than 50 years. In patients younger than 40 years, CMS1 was the most common subtype, whereas CMS3 and CMS4 were uncommon (P = .003). CMS2 was relatively stable across age groups. Early-onset patients with inflammatory bowel disease were more likely to have mucinous or signet ring histology (OR, 5.54; 95% CI, 2.24-13.74; P = .0004) and less likely to have APC mutations (OR, 0.24; 95% CI, 0.07-0.75; P = .019) in comparison with early-onset patients without predisposing conditions. CONCLUSIONS: Early-onset CRC is not only distinct from traditional CRC: special consideration should be given to and further investigations should be performed for both very young patients with CRC (18-29 years) and those with predisposing conditions. The etiology of the high rate of CMS1 in patients younger than 40 years deserves further exploration.

Colorectal cancer mutations are associated with survival and recurrence after pulmonary metastasectomy.

BACKGROUND AND OBJECTIVES: While knowledge has grown extensively regarding the impact of mutations on colorectal cancer prognosis, their role in outcomes after pulmonary metastasectomy (PM) remains minimally understood. We sought to determine the prognostic role of mutant disease on survival and recurrence after metastasectomy. METHODS: Patients with available tumor sequencing profiles who underwent PM for colorectal cancer at a single institution from 2011 to 2017 were reviewed. Various demographic and clinicopathologic factors, as well as mutational status, were tested in the Cox regression analyses to identify predictors of survival and disease-free survival (DFS). RESULTS: A total of 130 patients met inclusion criteria, among whom 78 (60%) were male and the mean age was 57 years. The median survival time and 5-year survival rate were 58.2 months and 47%, respectively. A single pulmonary nodule was present in 54%. Disease recurrence occurred for 87 (67%) patients, including 75 (58%) who had at least one lung recurrence after metastasectomy at a median time to recurrence of 19.4 months. Upon multivariable analysis, RAS and TP53 mutations were associated with shorter survival DFS, while APC is associated with prolonged survival. CONCLUSIONS: After metastasectomy for colorectal cancer, mutations in RAS, TP53, and APC play an important role in survival and recurrence.

Role of Immunotherapy in the Treatment of Squamous Cell Carcinoma of the Anal Canal.

Anal cancer is a rare malignancy for which cisplatin with 5-fluorouracil is the recommended treatment for patients with metastatic disease. Because most cases of anal cancer are linked to prior infection with oncogenic strands of the human papillomavirus, immunotherapeutic approaches have been of great interest in the development of new treatments for this virally driven tumor. This article reviews the early successes of anti-PD-1 therapies and adoptive T-cell therapies for metastatic anal cancer as a potential foundation for novel combination immunotherapy trials in the future.

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study.

BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. METHODS: We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. RESULTS: We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. INTERPRETATION: To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. FUNDING: National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Association of CpG island methylator phenotype and EREG/AREG methylation and expression in colorectal cancer.

BACKGROUND: High EREG and AREG expression, and left-sided primary tumours are associated with superior efficacy of anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (CRC), but a unifying explanation of these findings is lacking. METHODS: RNA-seq, gene expression arrays, and DNA methylation profiling were completed on 179 CRC tumours. Results were validated using independent The Cancer Genome Atlas data sets. An independent cohort of 198 KRAS wild-type metastatic CRC tumours was tested for CpG island methylator phenotype (CIMP) status, and progression-free survival (PFS) with the first anti-EGFR regimen was retrospectively determined. RESULTS: EREG and AREG expression was highly inversely correlated with methylation and was inversely associated with right-sided primary tumour, BRAF mutation, and CIMP-high status. Treatment of CRC cell lines with hypomethylating agents decreased methylation and increased expression of EREG. Inferior PFS with anti-EGFR therapy was associated with CIMP-high status, BRAF mutation, NRAS mutation, and right-sided primary tumour on univariate analysis. Among known BRAF/NRAS wild-type tumours, inferior PFS remained associated with CIMP-high status (median PFS 5.6 vs 9.0 mo, P=0.023). CONCLUSIONS: EREG and AREG are strongly regulated by methylation, and their expression is associated with CIMP status and primary tumour site, which may explain the association of primary tumour site and EREG/AREG expression with anti-EGFR therapy efficacy.

Multimodal approach and long-term survival in a patient with recurrent metastatic acinar cell carcinoma of the pancreas: A case report.

Pancreatic acinar cell carcinoma is an uncommon neoplasm of the exocrine pancreas associated with a poor prognosis, especially when found to be metastatic. Since there are a lack of large studies and prospective, randomized data, no consensus treatment guidelines are available. Here, we report a case of a patient with recurrent metastatic acinar cell carcinoma involving the liver who had presented initially with pancreatic panniculitis. She received chemotherapy with capecitabine and oxaliplatin prior to resection of her primary tumor and liver metastases, after which she experienced a 30 months recurrence-free survival. Upon relapse, she was treated with a combination of capecitabine and oxaliplatin followed by maintenance capecitabine. Now, more than seven years after initial diagnosis, the patient remains stable without evidence of active disease. This case highlights the possibility of therapeutic success even for a patient initially deemed unresectable due to a poor performance status who responded to fluoropyrimidine-based therapy.

Clinicopathologic Features Associated With Human Papillomavirus/p16 in Patients With Metastatic Squamous Cell Carcinoma of the Anal Canal.

BACKGROUND: The incidence of anal carcinoma in the U.S. continues to increase steadily, and infection with the human papillomavirus (HPV) is an established risk factor for the development of anal carcinoma. However, the clinicopathologic characteristics of patients with metastatic squamous cell carcinoma of the anal canal according to HPV status have not yet been defined. MATERIALS AND METHODS: The records of patients treated for metastatic squamous cell carcinoma of the anal canal at the MD Anderson Cancer Center from June 2005 to August 2013 were reviewed. The patients were tested for the presence of HPV DNA by in situ hybridization and/or the p16 oncoprotein by immunohistochemistry. Associations between the presence of HPV and clinicopathologic attributes were measured. RESULTS: Of the 72 patients reviewed, 68 tumors (94%) had detectable HPV. Patients with HPV-negative tumors were more likely to be of nonwhite ethnicity (odds ratio, 8.7) and have a strong (>30 pack-year) tobacco history (odds ratio, 8.7). A trend toward improved survival from the time of diagnosis of metastatic disease was noted among patients with HPV-positive tumors. CONCLUSION: Most patients with metastatic anal cancer had detectable HPV, with differences in tobacco history and ethnicity detected according to HPV status. The high frequency of HPV positivity for patients with metastatic anal cancer has important implications for novel immunotherapy treatment approaches, including ongoing clinical trials with immune checkpoint blockade agents using antibodies targeting the programmed death-1 receptor. IMPLICATIONS FOR PRACTICE: Previous studies investigating the clinical features of patients with anal cancer focused on those with early-stage disease. The present study characterizes, for the first time, clinical and pathological features according to human papillomavirus (HPV) status for patients with metastatic anal cancer. A high frequency of HPV-positive tumors and correlations between HPV status and both ethnicity and tobacco history was found. No standard-of-care therapy is available for patients with metastatic anal cancer, and most receive cytotoxic chemotherapy. The high prevalence of HPV in the current population generates optimism for ongoing clinical trials investigating the role of immune checkpoint blockade agents as a novel treatment approach for this disease.

Src activity is modulated by oxaliplatin and correlates with outcomes after hepatectomy for metastatic colorectal cancer.

BACKGROUND: The nonreceptor tyrosine kinase Src regulates multiple pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. It is robustly activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance in vitro and in vivo, but not after 5-fluorouracil (5-FU) alone. However, activation of Src and its substrate focal adhesion kinase (FAK) in metastatic colorectal cancer treated with oxaliplatin has not been investigated. We retrospectively evaluated the activation of Src and FAK in hepatic metastases of colorectal cancer and correlated these findings with the clinical outcomes of patients treated with oxaliplatin. METHODS: Samples from 170 hepatic resections from patients with metastatic colorectal cancer from two cohorts were examined by IHC for expression of Src, activated Src (pSrc), FAK, and activated FAK (pFAK). Patients in the first cohort (120 patients) were analyzed for immunohistochemical protein expression and for survival outcomes. In the second cohort, tissue was collected from 25 patients undergoing sequential hepatic metastasectomies (n = 50). RESULTS: In the first cohort, Src activation was positively correlated with pFAK expression (P = 0.44, P < 0.001). Patients pretreated with oxaliplatin and 5-FU demonstrated increased expression of pFAK (P = 0.017) compared with patients treated with 5-FU alone or irinotecan/5-FU. Total Src expression was associated with the number of neoadjuvant cycles of oxaliplatin (P = 0.047). In the second cohort, pFAK expression was higher following exposure to oxaliplatin. When patients were stratified by expression of pFAK and pSrc, an inverse relationship was observed between relapse-free survival rates and levels of both pFAK (21.1 months, 16.5 months, and 7.4 months for low, medium, and high levels of pFAK, respectively; P = 0.026) and pSrc (19.6 months, 13.6 months, and 8.2 months, respectively; P = 0.013). No differences in overall survival were detected. CONCLUSIONS: Patients administered neoadjuvant oxaliplatin demonstrated higher levels of Src pathway signaling in hepatic metastases, a finding associated with poorer relapse-free survival. These results are consistent with prior in vitro studies and support the idea that combining Src inhibition with platinum chemotherapy warrants further investigation in metastatic colorectal cancer.