Patrick McKay Boland

The emerging role of neoadjuvant chemotherapy for rectal cancer

Locally advanced rectal cancer remains a substantial public health problem. Historically, the disease has been plagued by high rates of both distant and local recurrences. The standardization of pre-operative chemoradiation and transmesorectal excision (TME) have greatly lowered the rates of local recurrence. Efforts to improve treatment through use of more effective radiosensitizing therapies have proven unsuccessful in rectal cancer. Presently, due to improved local therapies, distal recurrences represent the dominant problem in this disease. Adjuvant chemotherapy is currently of established benefit in colorectal cancer. As such, adjuvant chemotherapy, consisting of fluoropyrimidine and oxaliplatin, represent the standard of care for many patients. However, after pre-operative chemoradiotherapy and rectal surgery, the administration of highly effective chemotherapy regimens has proven difficult. For this reason, novel neoadjuvant approaches represent appealing avenues for investigation. Strategies of neoadjuvant chemotherapy alone, neoadjuvant chemotherapy followed by chemoradiation and neoadjuvant chemoradiation followed by chemotherapy are under investigation. Initial encouraging results have been noted, though definitive phase III data is lacking.

Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas

Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with in situ hybridization. Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well.

Molecular profiling of neuroendocrine malignancies to identify prognostic and therapeutic markers: a Fox Chase Cancer Center Pilot Study

Background:The rarity of neuroendocrine malignancies limits the ability to develop new therapies and thus a better understanding of the underlying biology is critical.Methods:Through a prospective, IRB-approved protocol, patients with neuroendocrine malignancies underwent next-generation sequencing of their tumours to detect somatic mutations (SMs) in 50 cancer-related genes. Clinicopathologic correlation was made among poorly differentiated neuroendocrine carcinomas (NECs/poorly differentiated histology and Ki-67 >20%) and pancreatic neuroendocrine tumours (PanNETs/Ki67 ⩽20%) and non-pancreatic neuroendocrine tumours (NP-NETs/Ki67 ⩽20%).Results:A total of 77 patients were enrolled, with next-generation sequencing results available on 63 patients. Incidence of SMs was 83% (19 out of 23) in poorly differentiated NECs, 45% (5 out of 11) in PanNETs and 14% (4 out of 29) in NP-NETs. TP53 was the most prevalent mutation in poorly differentiated NECs (57%), and KRAS (30%), PIK3CA/PTEN (22%) and BRAF (13%) mutations were also found. Small intestinal neuroendocrine tumours (Ki67 <2%/n=9) did not harbour any mutations. Prevalence of mutations correlated with higher risk of progression within the previous year (32% (low risk) vs 11% (high risk), P=0.01) and TP53 mutation correlated with worse survival (2-year survival 66% vs 97%, P=0.003).Conclusions:Poorly differentiated NECs have a high mutation burden with potentially targetable mutations. The TP53 mutations are associated with poor survival in neuroendocrine malignancies. These findings have clinical trial implications for choice of therapy and prognostic stratification and warrant confirmation.

Esophageal carcinoma: are modern targeted therapies shaking the rock?

Purpose of review Our current review aims to outline recent progress in the development of modern targeted therapeutic regimens for esophageal cancer. Recent findings Esophageal cancers demonstrate marked molecular heterogeneity. Modern technology increasingly allows us to identify subgroups of patients whose tumors fit particular molecular profiles. Tumor-based human epidermal growth factor receptor 2 (HER-2) analysis has become a standard part of the work-up for patients with tumors of the esophagogastric junction. The anti-HER-2 antibody, trastuzumab, when added to a chemotherapeutic regimen combining a fluoropyrimidine and platinum, provides a survival benefit for those patients with HER-2 overexpression and/or amplification. Despite large coordinated efforts to establish the efficacy of additional targeted therapeutics, to this point minimal additional benefit has been realized in affecting prominent molecular targets, such as vascular endothelial growth factor and epidermal growth factor receptor, in esophageal cancer. Multiple targets of interest remain under investigation with some early encouraging data. These targets include mammalian target of rapamycin, c-MET, insulin like growth factor 1 receptor and cytotoxic T-lymphocyte antigen 4. Additional improvements in therapy may stem from improved patient selection for combinations of standard cytotoxic regimens, such as platinum-based regimens. Summary Targeted therapeutics have yielded early benefit, but further progress will require a deeper understanding of this disease, improved identification of subpopulations who may derive greater benefit, and continued multicenter efforts to conduct the necessary clinical investigations.

Genetic counselors' (GC) knowledge, awareness, understanding of clinical next-generation sequencing (NGS) genomic testing.

Genomic tests are increasingly complex, less expensive, and more widely available with the advent of next‐generation sequencing (NGS). We assessed knowledge and perceptions among genetic counselors pertaining to NGS genomic testing via an online survey. Associations between selected characteristics and perceptions were examined. Recent education on NGS testing was common, but practical experience limited. Perceived understanding of clinical NGS was modest, specifically concerning tumor testing. Greater perceived understanding of clinical NGS testing correlated with more time spent in cancer‐related counseling, exposure to NGS testing, and NGS‐focused education. Substantial disagreement about the role of counseling for tumor‐based testing was seen. Finally, a majority of counselors agreed with the need for more education about clinical NGS testing, supporting this approach to optimizing implementation.

Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) in colorectal cancer: Evidence-based review of patient selection and treatment algorithms

Cytoreduction and heated intraperitoneal chemotherapy (CS/HIPEC) is increasingly utilized as a treatment strategy for patients with peritoneal metastases from various primary tumor sites. For this heterogenous procedure, related to patient characteristics, patient selection, and the extent of surgical completeness of cytoreduction, high level evidence (ex: multiple randomized controlled trials) is not available to support efficacy. This review of the available literature supporting application of the procedure, focusing on colorectal cancer, provides a summary of current evidence for patient selection and treatment algorithms based on patient presentation.

Predicting Individualized Postoperative Survival for Stage II/III Colon Cancer Using a Mobile Application Derived from the National Cancer Data Base.

BACKGROUND Prediction calculators estimate postoperative survival and assist the decision-making process for adjuvant treatment. The objective of this study was to create a postoperative overall survival (OS) calculator for patients with stage II/III colon cancer. Factors that influence OS, including comorbidity and postoperative variables, were included. STUDY DESIGN The National Cancer Data Base was queried for patients with stage II/III colon cancer, diagnosed between 2004 and 2006, who had surgical resection. Patients were randomly divided to a testing (nt) cohort comprising 80% of the dataset and a validation (nv) cohort comprising 20%. Multivariable Cox proportional hazards regression of nt was performed to identify factors associated with 5-year OS. These were used to build a prediction model. The performance was assessed using the nv cohort and translated into mobile software. RESULTS A total of 129,040 patients had surgery. After exclusion of patients with carcinoma in situ, nonadenocarcinoma histology, more than 1 malignancy, stage I or IV disease, or missing data, 34,176 patients were used in the development of the calculator. Independent predictors of OS included patient-specific characteristics, pathologic factors, and treatment options, including type of surgery and adjuvant therapy. Length of postoperative stay and unplanned readmission rates were also incorporated as surrogates for postoperative complications (1-day increase in postoperative stay, hazard ratio [HR] 1.019, 95% CI 1.018 to 1.021, p < 0.001; unplanned readmission vs no readmission HR 1.35, 95% CI 1.25 to 1.45, p < 0.001). Predicted and actual 5-year OS rates were compared in the nv cohort with 5-year area under the curve of 0.77. CONCLUSIONS An individualized, postoperative OS calculator application was developed for patients with stage II/III colon cancer. This prediction model uses nationwide data, culminating in a highly comprehensive, clinically useful tool.

Age-related rates of colorectal cancer and the factors associated with overall survival

Background The purpose of this study was to identify differences in both demographic and pathologic factors associated with the age-related rates of colorectal cancer (CRC) and overall survival (OS). Methods The National Cancer Data Base (NCDB), 2004-2013, was queried for patients with CRC. Patients were stratified by age (≤50 vs. ≥60 years). Multivariable analysis was performed to identify factors associated with OS. Results A total of 670,030 patients were included; 488,121 with colon, and 181,909 with rectal or rectosigmoid cancer. For colon cancer, patients ≤50 years had higher proportions of pathologic stage III and IV disease than patients ≥60 (III: 33.7% vs. 28.6%, IV: 25.5% vs. 14.3%, respectively; P≤0.001). Similar differences were found for patients with rectal cancer (III: 35.8% vs. 28.6%, IV: 16.5% vs. 11.6%, respectively for age ≤50 and ≥60 years; P≤0.001). More aggressive pathologic factors were identified in the ≤50 cohort and were associated with worse OS, including higher tumor grade, lymphovascular invasion (LVI), perineural invasion (PNI), and elevated serum carcinoembryonic antigen (CEA). Disparities associated with OS were also identified for both colon and rectal cancer. For patients ≤50 with CRC, African-American and Hispanic race, lower income and lower education were associated with increased risk of mortality compared to the ≥60 cohort. Conclusions There are clear differences in biological factors and in racial and socioeconomic disparities of patients with early onset CRC. Earlier screening should be seriously considered in patients under 50 years who are African-American and Hispanic, as these populations present with more aggressive and advanced disease.

Recent progress in Lynch syndrome and other familial colorectal cancer syndromes

The current understanding of familial colorectal cancer was limited to descriptions of affected pedigrees until the early 1990s. A series of landscape‐altering discoveries revealed that there were distinct forms of familial cancer, and most were related to genes previously not known to be involved in human disease. This review largely focuses on advances in our understanding of Lynch syndrome because of the unique relationship of this disease to defective DNA mismatch repair and the clinical implications this has for diagnostics, prevention, and therapy. Recent advances have occurred in our understanding of the epidemiology of this disease, and the advent of broad genetic panels has altered the approach to germline and somatic diagnoses for all of the familial colorectal cancer syndromes. Important advances have been made toward a more complete mechanistic understanding of the pathogenesis of neoplasia in the setting of Lynch syndrome, and these advances have important implications for prevention. Finally, paradigm‐shifting approaches to treatment of Lynch‐syndrome and related tumors have occurred through the development of immune checkpoint therapies for hypermutated cancers. CA Cancer J Clin 2018;68:217–231.

Adjuvant Chemotherapy Is Associated With Improved Overall Survival in Locally Advanced Rectal Cancer After Achievement of a Pathologic Complete Response to Chemoradiation

Micro‐Abstract Patients with rectal cancer and a complete response (pCR) to chemoradiation have an excellent prognosis. Adjuvant chemotherapy is controversial and used only in a few cases. The results of the present study have demonstrated associations between survival and age, comorbidities, carcinoembryonic antigen, and chemotherapy use in this population. Thus, chemotherapy appears to be underused in the pCR setting. Background In locally advanced rectal adenocarcinoma, 15% to 20% of patients treated with neoadjuvant chemoradiation (nCRT) achieve a pathologic complete response (pCR). The benefit of adjuvant chemotherapy is controversial in rectal cancer. Our objective was to evaluate the effect of clinical risk factors and adjuvant chemotherapy usage on the outcomes of the pCR patient population. Patients and Methods We performed a retrospective study using the National Cancer Data Base from 2006 to 2013. The primary outcome was overall survival (OS). The association between OS and patient characteristics (demographics, tumor variables, and treatment) was examined using multivariable Cox regression modelling. Results A total of 2891 patients were identified who had achieved a pCR. Of these 2891 patients, 2102 received nCRT and 789 received nCRT followed by adjuvant chemotherapy. The median follow‐up duration was 43.2 months. The factors significantly associated with OS included age (P < .001), gender (P = .011), Charlson‐Deyo comorbidity score (P < .001), grade (P = .029), clinical T stage (P = .030), carcinoembryonic antigen negativity (P = .002), and receipt of adjuvant chemotherapy (P < .001). Nodal status was not significantly associated with survival. The 5‐year OS rate was 94% in the nCRT plus adjuvant group compared with 84% in the nCRT‐alone group. Adjuvant chemotherapy was more likely to be given to younger patients (aged < 60 years), higher grade, lower Charlson‐Deyo comorbidity score, elevated carcinoembryonic antigen level, higher clinical T stage, and higher clinical N stage. Conclusion Our findings showed a significant improvement in OS for patients who received nCRT plus adjuvant chemotherapy compared with those who received nCRT alone. The nCRT plus adjuvant patients were more likely to be younger, have a lower comorbidity score, have clinical ≥ T3 disease, and have clinical node‐positive disease. Thus, a selection bias could have been present. Nonetheless, even in the setting of already excellent outcomes, for patients with locally advanced rectal adenocarcinoma who achieve a pCR, the additional benefit of adjuvant chemotherapy should be weighed against the potential for toxicity.