Tag: Colon Cancer

Location of Primary Tumor in the Colon Predicts Survival and Choice of Treatment in Metastatic Colorectal Cancer

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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 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. Several published studies have demonstrated a nearly 20% reduced risk of death for patients diagnosed with left sided colon cancer compared with those who had right sided tumors. Venook and colleagues had previously presented their findings from a retrospective evaluation of the phase III 80405 clinical trial which included data from 1,025 metastatic ColoRectal Cancer patients with KRAS wild-type disease. The researchers assessed the impact of tumor location on Overall and Progression Free Survival in this group of patients. The median age was 59 yrs and 293 patients had a right-sided primary tumor (location in the cecum to hepatic flexure) and 732 patients had a left-sided primary tumor (location in the splenic flexure to rectum). It was noted that patients with tumors originating in the right side of the colon had much shorter median Overall Survival (19.4 months) compared to patients with left-sided tumors (33.3 months), (HR=1.60; P<0.001), with a 14 month survival improvement in the left versus right-sided primary tumors, for patients with metastatic disease. Tumor location in the colon also had a bearing on response to ERBITUX® (Cetuximab) and AVASTIN® (Bevacizumab). For the patient group who received ERBITUX®, the median Overall Survival (OS) was 36 months for patients with left-sided tumors but only 16.7 months for patients with right-sided tumors. For those who received AVASTIN®, the median OS was 31.4 months for patients with left-sided tumors and 24.2 months for those with right-sided tumors. The median Progression Free Survival was also influenced by the site of the primary tumor and was 11.5 months for left-sided tumors versus 8.9 months for right-sided tumors in the overall cohort of patients (HR = 1.26; P = 0.002). It was concluded that the biology of tumors originating in the right colon may be different from those originating in the left colon and regardless of KRAS mutational status, AVASTIN® based, first line chemotherapy regimen should be considered, for all patients with metastatic colorectal cancer, with a right-sided colon primary tumor and ERBITUX® should be avoided in this patient group.

Understanding that there is a difference in outcomes with biologic therapy, based on tumor location in the colon, the authors in this study evaluated the molecular variations of tumors arising in different parts of the left colon. Using protein expression, gene amplification and NextGen sequencing, 1,457 primary tumors (125 from splenic flexure to descending colon, 460 in the sigmoid colon and 872 in the rectum) were examined. MicroSatellite Instability (MSI) was measured by PCR and tumor mutational load was calculated using somatic nonsynonymous missense mutations.

They noted that the incidence of  to MSI significantly decreased from right colon (22%), to descending colon (7%),sigmoid colon (4%) to rectum (1%) and this was statistically significant (P=0.01). Rectal tumors had a higher frequency of TP53 and APC gene mutations and higher expression of TOPO1, ERCC1 and MGMT, compared to tumors in the descending colon. Compared to sigmoid colon tumors, rectal tumors had a higher expression of TOPO1, MGMT, TLE3 and TUBB3.

The authors concluded that tumors arising in the rectum have a distinct set of genetic alterations compared with other left colon tumors, and these distinct biologic entities may need to be addressed with individually tailored therapy. Molecular variances between rectal and left-sided colon cancers. Marshall J, Lenz H, Xiu J, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 522)

Dual Inhibition Improves Outcomes for Patients with BRAF-Mutated Colorectal Tumors

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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 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. 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 MSI-High tumors tend to have better outcomes. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy. Approximately 5-10% of all metastatic CRC tumors present with BRAF V600 mutations and BRAF V600 is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 25% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600 mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.

ZELBORAF® (Vemurafenib), is a selective oral inhibitor of mutated BRAF whereas ERBITUX® (Cetuximab) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). Preclinical studies have shown that adding CAMPTOSAR® (Irinotecan) to ZELBORAF® and ERBITUX®, in patients with refractory BRAF V600E metastatic CRC, led to a durable responses and this combination was safe and tolerable. However, both single agent ZELBORAF® and ERBITUX® were shown to have limited activity in this patient group.

Based on this scientific rationale, a phase II trial was conducted (SWOG 1406), in which 106 metastatic ColoRectal Cancer patients, with mutations in BRAF V600 and extended RAS wild-type, were enrolled. Patients were randomized to receive CAMPTOSAR® 180 mg/m2 IV every 14 days and ERBITUX® 500 mg/m2 IV every 14 days, with or without ZELBORAF® 960 mg orally twice daily. The median age was 62 years and about 50% of patients had received 1 prior regimen for metastatic or locally advanced unresectable metastatic CRC, and 39% had received prior treatment with CAMPTOSAR® . Prior therapy with anti-EGFR agent or RAF or MEK inhibitors was not allowed. Crossover from the control arm to the experimental group was allowed, after documented disease progression. The primary endpoint was Progression Free Survival.

The median Progression Free Survival was 4.4 months with the triplet, versus 2.0 months with CAMPTOSAR® plus ERBITUX® (HR=0.42; P =0.0002). The response rate was 16% versus 4%, and the Disease Control Rate was 67% versus 22% (P =0.001), with a higher Duration of Response with the addition of ZELBORAF® to CAMPTOSAR® and ERBITUX® (Triplet). Approximately 50% of the patients in the control group crossed over to the experimental group at the time of disease progression. Overall Survival data and efficacy at cross-over, data, remain immature. Patients in the experimental group (Triplet group) experienced more grade 3/4 toxicities such as neutropenia, anemia and nausea, and this increase was attributed to increased duration of exposure to therapy.

The authors concluded that the addition of ZELBORAF® to the combination of CAMPTOSAR® and ERBITUX® resulted in a 58% reduction in the risk of disease progression and a higher Disease Control Rate, suggesting that simultaneous EGFR and BRAF inhibition (Dual Inhibition) is effective in BRAF V600 mutated ColoRectal Cancer. Subgroup analysis will examine the role of CAMPTOSAR® pre-treatment and the outcomes of patients based on tumor MicroSatellite Instability. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Kopetz S, McDonough SL, Morris VK, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 520)

Influence of Tumor Genetics (MSI) on Prognostic Effect of BRAF and KRAS Mutations in Patients with Colon Cancer

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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. These tumors are susceptible to PD-1 blockade and respond to treatment with checkpoint inhibitors such as Pembrolizumab (N Engl J Med 372:2509-2520, 2015).

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 publication 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.

Location of Primary Tumor Predicts Survival and Choice of Treatment in Metastatic Colorectal Cancer

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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.

Venook and colleagues had previously presented data from the primary analysis of a phase III CALGB/SWOG 80405 study which compared AVASTIN®: (Bevacizumab) or ERBITUX® (Cetuximab), given in conjunction with FOLFOX (Leucovorin, 5-Fluorouracil, Oxaliplatin) or FOLFIRI (Leucovorin, 5-FU, Irinotecan), as first line treatment of metastatic colorectal cancer. This study showed that chemotherapy plus ERBITUX® resulted in similar Overall Survival (29.9 months) as chemotherapy plus AVASTIN® (29 months) as well as Progression Free Survival (PFS). The present publication is a retrospective evaluation from the phase III 80405 clinical trial which included data from 1,025 patients with KRAS wild-type disease. The researchers assessed the impact of tumor location on Overall and PFS in this group of patients. The median age was 59 yrs and 293 patients had a right-sided primary tumor (location in the cecum to hepatic flexure) and 732 patients had a left-sided primary tumor (location in the splenic flexure to rectum).

It was noted that patients with tumors originating in the right side of the colon had much shorter median Overall Survival (19.4 months) compared to patients with left-sided tumors (33.3 months), (HR=1.60; P<0.001), with a 14 month survival improvement in the left versus right-sided primary tumors, for patients with metastatic disease. Tumor location in the colon also had a bearing on response to ERBITUX® and AVASTIN®. For the patient group who received ERBITUX®, the median Overall Survival (OS) was 36 months for patients with left-sided tumors but 16.7 months for patients with right-sided tumors. For those who received AVASTIN®, the median OS was 31.4 months for patients with left-sided tumors and 24.2 months for those with right-sided tumors. The median PFS was also influenced by the site of the primary tumor and was 8.9 months for right-sided tumors versus 11.5 months for left-sided tumors in the overall cohort of patients (HR = 1.26; P = 0.002). In a separate analysis, the authors also evaluated data from an additional 213 patients in CALGB/SWOG 80405 study who harbored KRAS mutations. These patients were originally included in this study prior to knowledge that ERBITUX® only benefited KRAS wild-type tumors. In this group of patients, those with left-sided primary tumors again achieved a longer median OS (30.3 months) compared to 23.1 months, among patients with right-sided tumors.

It was concluded that the biology of tumors originating in the right colon may be different from those originating in the left colon with ERBITUX® showing superiority over AVASTIN® when combined with chemotherapy in KRAS wild-type patients with left-sided colon cancer, whereas patients with right-sided colon cancer appear to benefit more from AVASTIN® based chemotherapy regimen. Regardless of KRAS mutational status, AVASTIN® based, first line chemotherapy regimen should be considered, for all patients with metastatic colorectal cancer, with a right-sided primary tumor. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Venook AP, Niedzwiecki D, Innocenti F, et al. J Clin Oncol 34, 2016 (suppl; abstr 3504)

Influence of MSI on Prognostic Effect of BRAF and KRAS Mutations in Patients with Stage III Colon Cancer

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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.

Daily Aspirin May Improve Survival after Diagnosis of Colorectal Cancer

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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

Left Sided Colon Cancer Patients Have Better Outcomes than Those with Right Sided Tumors

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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

EGFR Inhibition may not be Effective Immediately after VEGF blockade in Metastatic ColoRectal Cancer

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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)

XELOX Adjuvant Chemotherapy Regimen Improves Overall Survival in Stage III Colorectal Cancer

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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

ASCO Recommends Extended RAS Gene Testing in Metastatic Colorectal Cancer

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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.