Tag: Colon Cancer

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. The role of adjuvant chemotherapy in patients with Stage III ColoRectalCancer (CRC) has been well established, with improvement in Disease Free Survival (DFS) and Overall Survival (OS). However, not all patients equally benefit from this therapy. Patients with MSI (Micro Satellite Instability) tumor phenotype have better survival when cancer is at an earlier stage although this beneficial effect in Stage III colon cancer remains unclear.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an autosomal dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2.

Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations because KRAS mutations are predictive of resistance to EGFR targeted therapy and BRAF V600E is recognized as a marker of poor prognosis in this patient group. BRAF mutations occur in approximately 45% of patients with sporadic colorectal cancer with MSI but not seen in patients with Lynch syndrome. The prognostic effect of these mutations in early stage disease has however remained controversial. This is a Post Hoc Analysis of the PETACC-8 study, a randomized phase III trial, in which patients with resected Stage III colon cancer received treatment with adjuvant FOLFOX with or without Cetuximab. The authors in this publication examined the prognostic effect of BRAF and KRAS mutations in this patient population, as it relates to MSI of the tumor.

The PETACC-8 trial enrolled 2559 patients with surgically resected colon cancer, treated with adjuvant FOLFOX chemotherapy regimen. The median age was 60 years. MisMatch Repair, BRAF V600E, and KRAS exon 2 mutational status, were determined on tumor blocks that were collected prospectively from the enrolled patients. MSI phenotype was noted in 9.9% (N=177), KRAS mutations in 33.1% (N=588) and BRAF V600E mutations in 9% (N=148) of the patients. The primary end point was Disease Free Survival (DFS) and Overall Survival (OS), as it relates to these mutations.

In multivariate analysis, MSI and BRAF V600E mutations for DFS were not prognostic, whereas KRAS mutation was associated with significantly shorter DFS (P<0.001) and OS (P=0.008). The subgroup analysis showed that in patients with Micro Satellite Stable (MSS) tumors, DFS and OS was inferior among those with KRAS and BRAF V600E mutation and were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (P=0.04), but not OS (P=0.08).

The authors based on this large analysis of patients with Stage III colon cancer receiving FOFOX adjuvant chemotherapy, concluded that BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with Micro Satellite Stable (MSS) tumors, but not in patients with MSI tumors. Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab. A Post Hoc Analysis of the PETACC-8 Trial. Taieb J, Zaanan A, Le Malicot, et al. JAMA Oncol. 2016;2:643-653.

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Several epidemiological studies as well as randomized controlled trials have shown that Aspirin and NonSteroidal Anti-Inflammatory Drugs (NSAIDs) reduce the incidence of ColoRectal Cancer (CRC) and CRC associated mortality. Nonetheless, use of aspirin for the primary prevention of CRC, is not routinely recommended, for the fear of aspirin-induced gastric and cerebral hemorrhages. Even though the benefits of Aspirin in the primary prevention of CRC remains well established, the role of Aspirin in secondary prevention in patients with CRC (after the diagnosis of CRC) is unclear. Platelets have long been implicated in the mechanism of tumor metastases. More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of COX-2. Daily low dose Aspirin inhibits COX-1 and COX-2. It is postulated that Aspirin also works by COX-independent mechanisms such as, the inhibition of NF-kB and Wnt/ β-catenin signaling, which may play a role in its chemopreventive properties.

The authors conducted this trial to evaluate the association between Aspirin use after diagnosis of CRC and CRC-Specific Survival (CSS) and Overall Survival (OS), in the largest group of patients ever studied. The study authors in this retrospective, population-based study identified 24,495 patients in the Cancer Registry of Norway, diagnosed with ColoRectal Cancer from 2004 through 2011 and a total of 23,162 patients diagnosed with CRC were included. Using the Norwegian Prescription Database, the authors were then able to establish that 6,102 patients in this large cohort had documented exposure to Aspirin. Exposure to Aspirin was defined as a prescription for more than 6 months of Aspirin, following a diagnosis of CRC. The median follow up was 3 years.

The authors performed a multivariate regression analysis controlling for age, gender, tumor stage, tumor differentiation and noted that exposure to Aspirin post-diagnosis, independently improved ColoRectal Cancer-Specific Survival (HR=0.85; P<0.001) and Overall Survival (HR=0.95; P<0.076). Patients who used Aspirin both before and after diagnosis of CRC had additional improvement in ColoRectal Cancer-Specific Survival (HR= 0.77; P<0.001) and Overall Survival (HR=0.86; P<0.001). Further, patients with poorly and moderately differentiated tumors experienced the greatest benefits of Aspirin exposure, as well as those with stage II disease. The researchers were also able to demonstrate that Aspirin use was most beneficial in the first 2 to 3 years after diagnosis.

It was concluded that Aspirin use after the diagnosis of ColoRectal Cancer, is independently associated with improved Colorectal Cancer-Specific Survival and Overall Survival. Because of the increased risk for bleeding, the risk-benefit should be assessed before Aspirin is routinely recommended to this patient population. Aspirin as Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study. Bains SJ, Mahic M, Myklebust TA, et al. Published online before print May 31, 2016, doi:10.1200/JCO.2015.65.3519JCO May 31, 2016 JCO653519

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Even though prognosis for patients with Colon Cancer has improved over the past two to three decades, it has remained unclear if improvement in survival was greater for Left sided Colon Cancer versus cancer originating in the Right hemicolon. To address this question, the authors in this study used the Geneva population-based registry and collected the data on all Colon Cancer patients from 1980-2006. They then compared outcomes ided Tumorsin 3396 patients with proximal (Right-sided) and distal (Left-sided) Colon Cancer. In the study population, 1,334 patients (39%) had Right-sided tumors and 2,062 (61%) had Left-sided tumors. Colon Cancer specific survival was then determined and compared, taking into consideration tumor and treatment characteristics of Left and Right sided tumors, as well as putative confounding variables. The authors also compared changes in survival between Colon Cancer location in early and late years of this observation study.

At the beginning of the study period (1980s), the 5-year specific survival was identical for Right and Left sided Colon Cancers (49% versus 48%). However, over the course of the study period, there was a marked improvement in survival, for patients with Left-sided cancers (HR=0.42; P<0.001), but this benefit was not noted in Right-sided Colon Cancer patients (HR=0.76; P=0.69). As such, distal Colon Cancer (Left sided) had a better prognosis than patients with proximal or Right sided Colon Cancer (Hazard Ratio for Left versus Right Colon Cancer = 0.81; P<0.001).

The authors concluded from this study that survival of patients with Right Colon Cancer did not improve since 1980, and tend to have the worse prognosis of all Colon Cancer patients. Therefore, change in treatment strategy is warranted for this patient subgroup. Right colon cancer: left behind. Gervaza P, Usel M, Rapiti E, et al. European Journal of Surgical Oncology 2016;doi:10.1016/j.ejso.2016.04.002

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,000 new cases of ColoRectal Cancer will be diagnosed in the United States in 2016 and over 49,000 patients are expected to die of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now becoming clear that even among the KRAS Wild Type patients, about 15% to 20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing is now recommended.

The CALGB/SWOG 80405 study reported that either ERBITUX® or AVASTIN® in combination with chemotherapy have equivalent Overall Survival benefit, when given as first line therapy, for patients with metastatic ColoRectal Cancer (mCRC), whose tumors are KRAS Wild Type. Consequently, the optimal first-line therapy for patients with KRAS Wild Type metastatic CRC still remains unclear. ERBITUX® has a similar activity across all treatment lines whereas AVASTIN® appears to lose its efficacy along the course of treatment lines. Although FOLFOX and FOLFIRI are equally effective as first line treatment for patients with metastatic CRC, FOLFOX might be more effective as second line treatment. Preclinical studies have suggested that a prior anti VEGF therapy, may lower sensitivity to a subsequent anti EGFR treatment.

The authors in a phase III randomized multicenter trial addressed these issues by comparing two different sequences of ERBITUX® and FOLFOX chemotherapy in KRAS Wild Type metastatic CRC patients, refractory to first line FOLFIRI chemotherapy and AVASTIN®. Patients with mCRC (N=110) were randomly assigned in a 1:1 ratio to receive CAMPTOSAR® (Irinotecan)/ERBITUX® as second line followed by FOLFOX-4 chemotherapy as third line (Arm A) or the reverse sequence (FOLFOX-4 chemotherapy second line followed by CAMPTOSAR®/ERBITUX® as third line – Arm B). The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS) and toxicity. It was noted that the median PFS in Arm A was 9.9 months compared to 11.3 months in Arm B (HR=0.85; P=0.42) and the median OS was 12.3 months in Arm A and 18.6 months in Arm B (HR=0.79; P=0.28). The Objective Response Rate in Arm A was 37% and in Arm B was 57% (P=0.05). Treatment was well tolerated with a low incidence of serious adverse events.

It was concluded that EGFR inhibition is not active immediately after VEGF blockade and therefore ERBITUX® is less effective immediately after AVASTIN®. The sequence of biological agents appears to be more important than the first-line chemotherapy choice. In RAS Wild Type metastatic CRC patients progressing after a first line AVASTIN® based therapy, ERBITUX® should be given in the third line setting or should be considered in first line treatment regimen. Efficacy of cetuximab immediately after bevacizumab: A phase III multicenter trial comparing two different sequences of cetuximab and FOLFOX in K-Ras WT metastatic colorectal cancer patients refractory FOLFIRI/bevacizumab. Cascinu S, Zaniboni A, Lonardi S, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 632)

SUMMARY: The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. Adjuvant chemotherapy for patients with resected locally advanced, node-positive (stage III) colon cancer has been the standard of care since 1990s with improved Overall Survival noted after 6 months of bolus schedule of 5-Fluouracil (5-FU) and Leucovorin. Subsequently, the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trials showed that the addition of ELOXATIN® (Oxaliplatin) to infusional 5- FU and Leucovorin (FOLFOX) or bolus 5-FU and Leucovorin (FLOX) significantly prolonged 3 year Disease Free Survival (DFS) when given in an adjuvant setting, in patients with stage II or III colon cancer. However, there was no significant Overall Survival (OS) benefit noted in the NSABP C-07 study.

XELOXA or NO16968 is a multinational, open-label, randomized phase III study, which only enrolled patients with stage III disease. Patients (N=1886) were randomly assigned to receive a more convenient XELOX regimen (N=944) or 5-FU and Leucovorin (N=942). The later regimen was considered the standard therapy when this trial was designed.The XELOX regimen consisted of a ELOXATIN® 130 mg/m2 given as a 2-hour IV infusion on day 1 and XELODA® (Capecitabine) 1,000 mg/m2 PO twice daily on days 1 to 14, of a 3 week cycle, for a total of eight cycles. The 5-FU/Leucovorin regimens could be either the Mayo Clinic or Roswell Park regimens. The Mayo Clinic regimen consisted of Leucovorin 20 mg/m2 and 5-FU 425 mg/m2 IV push on days 1-5, repeated every 4 weeks, for a total of six cycles. The Roswell Park regimen consisted of Leucovorin 500 mg/m2 given as a 2-hour infusion and 5-FU 500 mg/m2 IV push at 1 hour after the start of the Leucovorin infusion, repeated every week for six weeks, followed by a 2 week rest period, for a total of four 8-week cycles. The primary end point of this study was Disease Free Survival (DFS). Secondary end points were Overall Survival (OS), Relapse Free Survival (RFS) and safety.

The 3 year DFS data was published in 2011 and it was then noted that the addition of ELOXATIN® to oral Fluoropyrimidine, XELODA® improved DFS (HR=0.80; P=0.0045), similar to the previously published MOSAIC and NSABP C-07 trials. The authors in this publication reported the final efficacy data and biomarker analysis from the NO16968 trial comparing bolus 5-FU and Leucovorin with XELODA® plus ELOXATIN® (XELOX) in resected stage III colon cancer. The 7 year DFS rates were 63% and 56% in the XELOX and 5-FU/Leucovorin groups respectively (HR=0.80; P=0.004). The Overall Survival rates after a median follow up of 7 years were 73% and 67% in the XELOX and 5-FU/Leucovorin groups respectively (HR=0.83; P=0.04). It was noted that in the 498 patients who consented to the biomarker analysis, low tumor expression of DihydroPyrimidine Dehydrogenase was predictive for efficacy with XELOX regimen. There was however no statistically significant associations noted between any tumor biomarker and outcomes in the 5-FU/Leucovorin groups.

The authors concluded that in patients with resected stage III colon cancer, XELOX significantly improved Overall Survival compared to 5-FU/Leucovorin regimens and should be considered a standard adjuvant treatment option for patients with stage III disease. Tumor DihydroPyrimidine Dehydrogenase expression may be a clinically relevant biomarker for XELOX efficacy, but will require further evaluation. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial.Schmoll HJ, Tabernero J, Maroun J, et al. J Clin Oncol. 2015;33:3733-3740

SUMMARY: The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Patients with metastatic CRC, whose disease has progressed after treatment with standard therapies, have limited therapeutic options available, to treat their disease. Even though the Epidermal Growth Factor Receptor (EGFR) has been reported to be over expressed in 50-85% of the ColoRectal tumors, the intensity of ImmunoHistoChemical staining of EGFR in these tumors is not predictive of treatment response with EGFR directed antibody therapy such as ERBITUX® (Cetuximab) and VECTIBIX® (Panitumumab) and EGFR ImmunoHistoChemical staining should therefore not be a part of testing. The most common RAS oncogenes in human cancer are HRAS, KRAS, and NRAS. Mutations in HRAS are not common in colon cancer whereas KRAS and NRAS mutations are seen in colon cancer and tend to be mutually exclusive. It is also known that mutations in BRAF gene, which is downstream from RAS, may confer poor prognosis in colon cancer, regardless of therapy. It is estimated that approximately 40% of mCRC tumors harbor KRAS mutations and several studies had shown that metastatic ColoRectal Cancer (mCRC) tumors of patients harboring mutations in codon 12 or 13 of exon 2 of the KRAS gene, do not benefit from therapy with monoclonal antibodies directed against EGFR, when used as monotherapy or combined with chemotherapy. More recent studies have shown that KRAS mutations outside of exon 2 and mutations in NRAS are also predictive of lack of benefit with EGFR directed therapy.

The American Society of Clinical Oncology Provisional Clinical Opinion (PCO) offers clinical direction for practicing oncology Health Care Providers, after publication or presentation of potentially practice-changing data from major studies. This 2015 ASCO Provisional Clinical Opinion update is a concerted effort of several organizations together with ASCO and they include the College of American Pathologists (CAP), the American Society for Clinical Pathology (ASCP), and the Association for Molecular Pathology (AMP). The Provisional Clinical Opinion (PCO) was released following inclusion of a systematic review of 11 meta-analyses, two retrospective analyses, and two health technology assessments in patients with mCRC. These studies evaluated the outcomes for patients with mCRC with no mutation detected or presence of mutation in additional exons in KRAS and NRAS. The extended RAS gene testing included

1) KRAS exons 2 (codons 12 and 13) exons 3 (codons 59 and 61) and exons 4 (codons 117 and 146)

2) NRAS exons 2 (codons 12 and 13), exons 3 (codons 59 and 61) and exons 4 (codons 117 and 146)

Two mCRC studies, the PRIME trial and the CRYSTAL trial, in their analysis included both KRAS and NRAS mutation data. In the PRIME study, the median Overall Survival (OS) in patients with wild-type RAS mCRC treated with VECTIBIX® plus FOLFOX was 26.0 months compared with 20.2 months with FOLFOX alone (HR=0.78; P=0.04). The Progression Free Survival (PFS) in patients not harboring RAS mutations was 10.1 months with VECTIBIX® plus FOLFOX, compared with 7.9 months with FOLFOX alone (HR=0.72; P=0.004). In the CRYSTAL trial, the median OS with ERBITUX® plus FOLFIRI was 28.4 months compared to 20.2 months with FOLFIRI alone, in patients with wild-type RAS mCRC (HR=0.69). The PFS in patients without RAS mutations was 11.4 months with ERBITUX® plus FOLFIRI compared with 8.4 months with FOLFIRI alone (HR, 0.56). Both these studies have shown that EGFR directed monoclonal antibody therapy does not benefit patients with KRAS or NRAS mutations and may even have a detrimental effect in these patients.

It was concluded that the current evidence indicates that EGFR directed therapy with monoclonal antibodies, ERBITUX® and VECTIBIX® should only be considered for treatment of patients with mCRC, whose tumors have no mutations detected after extended RAS mutation analysis. It is recommended that KRAS and NRAS genotyping of tumor should be performed at diagnosis of stage IV disease, as anti-EGFR directed therapy has no role in stage I, II or III disease. BRAF V600E mutation has been associated with poor prognosis in mCRC patients and may also predict lack of response to anti-EGFR monclonal antibody therapy, and should be a part of genotyping, at diagnosis of stage IV disease. Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. Allegra CJ, Rumble RB, Hamilton SR, et al. Published online October 5, 2015. J Clin Oncol. doi: 10.1200/JCO.2015.63.9674.

SUMMARY: The FDA on September 22, 2015 approved LONSURF® (Trifluridine/Tipiracil) for the treatment of patients with metastatic ColoRectal Cancer (CRC), who have been previously treated with Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. The American Cancer Society estimates that approximately 133,000 new cases of ColoRectal Cancer (CRC) will be diagnosed in the United States in 2015 and close to 50,000 are expected to die of the disease. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Patients with metastatic CRC, whose disease has progressed after treatment with standard therapies, have limited therapeutic options available, to treat their disease.

LONSURF® is a combination of two agents – a novel oral nucleoside, Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride.

The RECOURSE study is a pivotal, global, phase III trial, in which 800 patients with metastatic ColoRectal Cancer, refractory to all standard therapies were randomly assigned in a 2:1 ratio to receive either LONSURF® (N=534) or placebo (N=266). Patients received LONSURF® 35mg/m2 or matching placebo orally, twice daily after meals, on Days 1-5 and 8-12 of each 28 day cycle. Treatment was continued until disease progression or unacceptable toxicity. Eligible patients had metastatic ColoRectal Cancer (mCRC), previously treated with chemotherapy and biological therapy, which included Fluoropyrimidine, Oxaliplatin and Irinotecan-based chemotherapy, an anti-VEGF biological therapy and if RAS wild-type, an anti-EGFR therapy. The primary endpoint of this study was overall survival and the secondary endpoint was progression-free survival.

It was noted that LONSURF® significantly improved Overall Survival compared to placebo (7.1 months vs 5.3 months; HR=0.68; P<0.001), with a 32% reduction in the risk of death. LONSURF® also significantly improved Progression Free Survival compared to placebo (HR = 0.47; P<0.001). The most common grade 3 or more adverse events were leukopenia (21%), anemia (18%) and febrile neutropenia (4%), noted in patients receiving LONSURF®. The authors concluded that LONSURF® significantly improved Overall Survival in patients with refractory metastatic ColoRectal Cancer, providing a novel oral therapeutic option for this patient group. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. Mayer RJ, Van Cutsem E, Falcone A, et al. N Engl J Med 2015; 372:1909-1919

SUMMARY: The American Cancer Society estimates that in the United States, for the year 2015, approximately 140,000 new cases of ColoRectal Cancer (CRC) will be diagnosed and close to 50,000 patients will die of the disease. The lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%). Lynch Syndrome (Hereditary NonPolyposis Colorectal Cancer – HNPCC), is an Autosomal Dominant, inherited disorder, associated with an increased risk of colorectal, endometrial, ovary, gastric, small bowel, pancreatic, brain, ureter or renal pelvis cancer. Approximately 3 to 5 percent of all cases of ColoRectal Cancer, are caused by Lynch Syndrome (LS) and 1 in 35 patients with newly diagnosed ColoRectal Cancer is related to Lynch Syndrome. Four MMR genes (MisMatch Repair genes), MLH1, MSH2, MSH6, and PMS2 are involved in the repair of mistakes that occur during DNA replication. When any of these genes are mutated, repair of DNA replication mistakes is prevented resulting in continuous division of abnormal cells and possibly cancer. The EPCAM gene lies next to the MSH2 gene on chromosome 2 and mutations in the EPCAM gene can cause the MSH2 gene to be inactivated, interrupting DNA repair and leading to accumulation of DNA replication errors and possible malignancy. Germline mutations in the MMR genes, is classically seen in Lynch Syndrome and results in microsatellite instability in tumors. Tumors are described as MSI-High when they have changes in 2 or more, of the 5 microsatellite markers. So, high levels of MSI within a tumor are suggestive of defective DNA mismatch repair. MSI-H is a hallmark of Lynch syndrome. However MSI-H is present in approximately 15% of patients with sporadic CRC. This is secondary to epigenetic silencing of MLH1 through promoter hypermethylation, rather than germline mutations in the MMR genes.

A Clinical Diagnosis of Lynch Syndrome can be made based on personal and family history if at least three relatives have a malignancy associated with Lynch Syndrome such as colorectal, endometrial, small bowel, ureter or renal pelvis cancer. In addition the following criteria should be met: • One relative must be a first-degree relative of the other two. • At least two successive generations must be affected. • At least one relative with a Lynch syndrome associated cancer should be diagnosed before 50 years of age. • Familial Adenomatous Polyposis should be excluded. • Tumors should be verified whenever possible. Because family history can sometimes be difficult to obtain or confirm, NCCN in those circumstances has recommended screening all newly diagnosed colorectal cancer patients for Lynch syndrome.

ImmunoHistoChemistry (IHC) staining can be performed on the tumor tissue for protein expression of the four MMR genes. IHC test is described as normal when all 4 mismatch repair proteins are normally expressed suggesting that an underlying mismatch repair gene mutation is unlikely. When IHC test is abnormal, it means that that at least one of the 4 mismatch repair proteins is not expressed and an inherited mutation may be present in the gene related to that protein. This can be further confirmed by mutation analysis of the corresponding gene. However, the lack of expression of MMR proteins by IHC is highly concordant with molecular MSI testing and IHC is therefore more practical and cost-effective. Tumors with loss of MMR protein expression or MSI-H are classified as MMR deficient (dMMR). Patients with sporadic tumors with MSI-H or MMR deficiency (dMMR) generally are older women with stage II disease and present with tumors in the proximal colon and the tumors are poor differentiated with increased number of tumor-infiltrating lymphocytes. These patients in retrospective studies had superior stage-adjusted survival compared to MMR proficient tumors. Further, single agent 5-Fluorouracil when given in an adjuvant setting was not beneficial in this patient group.

It should also be noted that a majority of colon cancer tumors that lack protein expression on IHC staining of MLH1 (often coexisting with loss of PMS2) are often due to an acquired genetic defect. If the IHC indicates absence of MLH1 protein expression, tumor should be tested for BRAF mutation V600E, which can be seen in sporadic colorectal cancers, but rarely found in patients who have Lynch Syndrome. Once a diagnosis of Lynch Syndrome is made, at risk family members should undergo colonoscopic evaluation at 20-25 years of age or 2-5 years prior to the earliest colon cancer, if it is diagnosed before age 25 and is repeated every 1-2 years. Prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) should be considered by women who have completed childbearing. NCCN Guidelines Version 1.2014 Lynch Syndrome