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Jaideep Sandhu, Chongkai Wang and Marwan Fakih

HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient’s response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non–HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC.

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Kristin K. Deeb, Jakub P. Sram, Hanlin Gao and Marwan G. Fakih

Specific genomic colorectal cancer alterations are increasingly linked to prognosis and/or response to specific anticancer agents. The identification of KRAS mutations as markers of resistance to epidermal growth factor receptor (EGFR) inhibitors has paved the way to the interrogation of numerous other markers of resistance to anti-EGFR therapy, such as NRAS, BRAF, and PI3KCA mutations. Other genomic and protein expression alterations have recently been identified as potential targets of treatment or as markers of chemotherapy or targeted-therapy resistance, including ERCC1 expression, c-Met expression, PTEN expression, HER2 amplification, HER3 expression, and rare KRAS mutations. As the number of distinct validated intratumor genomic assays increases, numerous molecular assays will need to be compiled into one multigene panel assay. Several companies and academic centers are now offering multigene assays to patients with metastatic colorectal cancer and other solid tumors. This article discusses the technology behind multigene assays, its limitations, its current advantages, and its potential in the clinical care of metastatic colorectal cancer.

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Jun Gong, Chongkai Wang, Peter P. Lee, Peiguo Chu and Marwan Fakih

Recent clinical evidence has demonstrated that microsatellite instability (MSI) or defective mismatch repair (MMR) and high tumor mutational load can predict response to the programmed cell death 1 (PD-1) receptor inhibitor pembrolizumab in metastatic colorectal cancer (mCRC). Mutations in polymerase ε (POLE), a DNA polymerase involved in DNA replication and repair, contribute to an ultramutated but microsatellite stable (MSS) phenotype in colorectal tumors that is uniquely distinct from MSI tumors. This report presents the first case in the literature describing a clinical response to pembrolizumab in an 81-year-old man with treatment-refractory mCRC characterized by an MSS phenotype and POLE mutation identified on genomic profiling by next-generation sequencing. On tumor immunostaining, a large amount of CD8-positive tumor infiltrating lymphocytes (TILs) were present, with >90% of these expressing PD-1. More than 99% of PD-L1 expression was identified on nontumor cells in the tumor microenvironment that were close to the PD-1–positive CD8 TILs. mCRC tumors harboring POLE mutations represent a hypermutated phenotype that may predict response to anti–PD-1 therapy.

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Justin A. Chen, Naseem Esteghamat, Edward J. Kim, Gabriel Garcia, Jun Gong, Marwan G. Fakih, Richard J. Bold and May T. Cho

Immune checkpoint inhibitors represent a newly established standard of care in patients with refractory metastatic colorectal cancer with mismatch repair deficiency and microsatellite instability. However, the use of immunotherapy is unclear in recipients of liver transplants with or without concurrent liver function abnormalities. Clinical trials investigating immunotherapy have mostly excluded liver transplant recipients and patients with abnormal liver function. This report presents the first case, to our knowledge, of a liver transplant patient with mismatch repair–deficient colon adenocarcinoma with liver metastases and concurrent abnormal liver function who safely responded to immunotherapy. We also review the literature on checkpoint inhibitor use in patients with other metastatic solid tumors after liver transplant and those with baseline liver function abnormalities. An increasing body of evidence supports the safety of checkpoint inhibition in patients with cancer and solid organ transplants, but further prospective studies are warranted. Use of immunotherapy in liver transplant recipients who have metastatic colorectal cancer with microsatellite instability is feasible but should be performed in a multidisciplinary team setting.

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Richard Li, Ashwin Shinde, Marwan Fakih, Stephen Sentovich, Kurt Melstrom, Rebecca Nelson, Scott Glaser, Yi-Jen Chen, Karyn Goodman and Arya Amini

Background: Anal adenocarcinoma is a rare malignancy with a poor prognosis, and no randomized data are available to guide management. Prior retrospective analyses offer differing conclusions on the benefit of surgical resection after chemoradiotherapy (CRT) in these patients. We used the National Cancer Database (NCDB) to analyze survival outcomes in patients undergoing CRT with and without subsequent surgical resection. Methods: Patients with adenocarcinoma of the anus diagnosed in 2004 through 2015 were identified using the NCDB. Patients with metastatic disease and survival <90 days were excluded. We analyzed patients receiving CRT and stratified by receipt of surgical resection. Logistic regression was used to evaluate predictors of use of surgery and to form a propensity score–matched cohort. Overall survival (OS) was compared between treatment strategies using Cox proportional hazards regression. Results: We identified 1,747 patients with anal adenocarcinoma receiving CRT, of whom 1,005 (58%) received surgery. Predictors of increased receipt of surgery included age <65 years, private insurance, overlapping involvement of the anus and rectum, N0 disease, and external-beam radiation dose ≥4,000 cGy. With a median follow-up of 3.5 years, 5-year OS was 61.1% in patients receiving CRT plus surgery compared with 39.8% in patients receiving CRT alone (log-rank P<.001). In multivariate analysis, surgery was associated with significantly improved OS (hazard ratio, −0.59; 95% CI, 0.50–0.68; P<.001). This survival benefit persisted in a propensity score–matched cohort (log-rank P<.001). Conclusions: In the largest series of anal adenocarcinoma cases to date, treatment with CRT followed by surgery was associated with a significant survival benefit compared with CRT alone in propensity score–matching analysis. Our findings support national guideline recommendations of neoadjuvant CRT followed by resection for patients with anal adenocarcinoma.

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Rahel Demisse, Neha Damle, Edward Kim, Jun Gong, Marwan Fakih, Cathy Eng, Leslie Oesterich, Madison McKenny, Jingran Ji, James Liu, Ryan Louie, Kit Tam, Sepideh Gholami, Wissam Halabi, Arta Monjazeb, Farshid Dayyani and May Cho

Treatment options for locally advanced rectal cancer have continued to consist largely of chemotherapy, chemoradiation, and/or surgical resection. For patients who are unable to undergo these therapeutic modalities or who do not to experience a response to them, treatment options are limited. We report 3 cases of mismatch repair–deficient (dMMR) locally advanced adenocarcinoma of the rectum that showed significant response with neoadjuvant immunotherapy–based systemic treatment. The first patient was not eligible for standard therapy because of a history of radiotherapy to the prostate with concurrent comorbidities and therefore received single-agent pembrolizumab. The second patient did not respond to total neoadjuvant chemoradiation and subsequently received combined nivolumab and ipilimumab. The third patient had a known family history of Lynch syndrome and presented with locally advanced rectal cancer and a baseline carcinoembryonic antigen level of 1,566 ng/mL. She was treated using neoadjuvant pembrolizumab and FOLFOX (folinic acid, fluorouracil, oxaliplatin). In this small series, we suggest that single-agent and combined-modality neoadjuvant immunotherapy/chemotherapy appear to be safe and effective treatment options for patients with (dMMR) locally advanced rectal cancer. Our findings encourage further studies to investigate the role of neoadjuvant immunotherapy as a viable treatment strategy in this population.

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Paul F. Engstrom, Juan Pablo Arnoletti, Al B. Benson III, Jordan D. Berlin, J. Michael Berry, Yi-Jen Chen, Michael A. Choti, Harry S. Cooper, Raza A. Dilawari, Dayna S. Early, Peter C. Enzinger, Marwan G. Fakih, James Fleshman Jr., Charles Fuchs, Jean L. Grem, James A. Knol, Lucille A. Leong, Edward Lin, Mary F. Mulcahy, Eric Rohren, David P. Ryan, Leonard Saltz, David Shibata, John M. Skibber, William Small Jr., Constantinos Sofocleous, James Thomas, Alan P. Venook and Christopher Willett

OverviewAn estimated 5290 new cases (2100 men and 3190 women) of anal cancer (involving the anus, anal canal, or anorectum) will occur in the United States in 2009, accounting for approximately 1.9% of digestive system cancers, and an estimated 710 deaths due to anal cancer. Although considered to be a rare type of cancer, the incidence rate of invasive anal carcinoma in the United States increased by approximately 1.6-fold for men and 1.5-fold for women from 1973-1979 to 1994-2000 (see Risk Factors, facing page).This manuscript summarizes the NCCN Clinical Practice Guidelines in Oncology for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. Other types of cancers occurring in the anal region are addressed in other NCCN guidelines (i.e., anal adenocarcinoma and anal melanoma are managed according to the NCCN Clinical Practice Guidelines in Oncology on Rectal Cancer and Melanoma, respectively). Except where noted, the recommendations in these guidelines are classified as category 2A, meaning that uniform NCCN consensus was present among the panel based on lower-level evidence that the recommendation is appropriate. The panel unanimously endorses patient participation in a clinical trial over standard or accepted therapy.Risk FactorsAnal carcinoma has been associated with human papilloma virus (HPV) infection (anal-genital warts); history of receptive anal intercourse or sexually transmitted disease; history of cervical, vulvar, or vaginal cancer; immunosuppression after solid organ transplantation or HIV infection; and smoking. Currently, the association between anal carcinoma and persistent infection with a high-risk form...
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Paul F. Engstrom, Juan Pablo Arnoletti, Al B. Benson III, Yi-Jen Chen, Michael A. Choti, Harry S. Cooper, Anne Covey, Raza A. Dilawari, Dayna S. Early, Peter C. Enzinger, Marwan G. Fakih, James Fleshman Jr., Charles Fuchs, Jean L. Grem, Krystyna Kiel, James A. Knol, Lucille A. Leong, Edward Lin, Mary F. Mulcahy, Sujata Rao, David P. Ryan, Leonard Saltz, David Shibata, John M. Skibber, Constantinos Sofocleous, James Thomas, Alan P. Venook and Christopher Willett

Colon Cancer Clinical Practice Guidelines in Oncology NCCN Categories of Evidence and Consensus Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus. Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement). Category 3: The recommendation is based on any level of evidence but reflects major disagreement. All recommendations are category 2A unless otherwise noted. Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Overview Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2009, an estimated 106,100 new cases of colon and 40,870 cases of rectal cancer will occur. During the same year, it is estimated that 49,920 people will die from colon and rectal cancer.1 Despite these statistics, mortality from colon cancer has decreased slightly over the past 30 years, possibly due to earlier diagnosis through screening and better treatment modalities. This manuscript summarizes the NCCN Clinical Practice Guidelines in Oncology for managing colon cancer. The guidelines begin with clinical presentation to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, adjuvant treatment, management of recurrent and metastatic disease, and patient surveillance. When reviewing these guidelines, clinicians should be aware of...
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Paul F. Engstrom, Juan Pablo Arnoletti, Al B. Benson III, Yi-Jen Chen, Michael A. Choti, Harry S. Cooper, Anne Covey, Raza A. Dilawari, Dayna S. Early, Peter C. Enzinger, Marwan G. Fakih, James Fleshman Jr., Charles Fuchs, Jean L. Grem, Krystyna Kiel, James A. Knol, Lucille A. Leong, Edward Lin, Mary F. Mulcahy, Sujata Rao, David P. Ryan, Leonard Saltz, David Shibata, John M. Skibber, Constantinos Sofocleous, James Thomas, Alan P. Venook and Christopher Willett

Rectal Cancer Clinical Practice Guidelines in Oncology NCCN Categories of Evidence and Consensus Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus. Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement). Category 3: The recommendation is based on any level of evidence but reflects major disagreement. All recommendations are category 2A unless otherwise noted. Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Overview In 2009 an estimated 40,870 new cases of rectal cancer will occur in the United States (23,580 cases in men; 17,290 cases in women). During the same year, an estimated 49,920 people will die from rectal and colon cancers.1 Although colorectal cancer is ranked as the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States, mortality from colorectal cancer has decreased during the past 30 years. This decrease may be due to earlier diagnosis through screening and better treatment modalities. The recommendations in these clinical practice guidelines are classified as category 2A except where noted, meaning that there is uniform NCCN consensus, based on lower-level evidence (including...
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Al B. Benson III, Tanios Bekaii-Saab, Emily Chan, Yi-Jen Chen, Michael A. Choti, Harry S. Cooper, Paul F. Engstrom, Peter C. Enzinger, Marwan G. Fakih, Moon J. Fenton, Charles S. Fuchs, Jean L. Grem, Steven Hunt, Ahmed Kamel, Lucille A. Leong, Edward Lin, Kilian Salerno May, Mary F. Mulcahy, Kate Murphy, Eric Rohren, David P. Ryan, Leonard Saltz, Sunil Sharma, David Shibata, John M. Skibber, William Small Jr, Constantinos T. Sofocleous, Alan P. Venook, Christopher G. Willett, Kristina M. Gregory and Deborah A. Freedman-Cass

The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel’s discussions regarding the treatment of localized disease for the 2013 update of the guidelines.