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 135,430 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 lifetime risk of developing ColoRectal Cancer (CRC) is about 1 in 20 (5%). 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.

The initial evaluation of patients with metastatic ColoRectal Cancer (CRC) includes Molecular diagnostic testing including testing for extended RAS (RAt Sarcoma) and RAF (Rapid Accelerated Fibrosarcoma) mutations. Next-Generation Sequencing (NGS) allows expanded mutational testing for RAS which includes KRAS, NRAS and HRAS. RAS mutations are predictive of resistance to EGFR targeted therapy. NGS is able to detect approximately 20% of the patients who were originally classified as having KRAS Wild-Type (WT) metastatic CRC but were subsequently found to have KRAS or NRAS mutations, thus predicting resistance to EGFR targeted therapy.

Approximately 10% of CRCs detected by NGS harbor BRAF V600E mutation and the detection of BRAF V600E mutation is recognized as a marker of poor prognosis in patients with metastatic CRC. RAS and BRAF V600E mutations occur in a mutually exclusive fashion. Patients with this molecular subtype of CRC are older than age 60 years, more frequently female, have a right-sided tumor with high-grade histology, and often have MicroSatellite Instability (MSI-H). These patients often have peritoneal metastasis and despite chemotherapeutic intervention have a shortened overall survival. These tumors have limited response to EGFR targeted therapy and current guidelines recommend against the use of anti-EGFR antibodies in BRAF V600E-mutated mCRC.

The significance of non-V600 BRAF mutations detected by NGS however has remained unclear. The authors in this multicenter, retrospective cohort study, pooled NGS data from three large US reference laboratories and attempted to establish the clinical characteristics of patients with non-V600 BRAF mutations. Using NGS databases from the Mayo Clinic (MC), The University of Texas MD Anderson Cancer Center (MDACC), and Foundation Medicine (FM) from 2013-2016, patients with non-V600 BRAF mutations from these three institutions were identified and pooled for the primary analysis. Out of a total of 9,643 patients with metastatic CRC who underwent NGS testing, 208 patients with non-V600 BRAF mutations and 133 patients with V600E BRAF mutations, were identified. This study also included 249 patients with Wild-Type BRAF metastatic CRC, for comparative analysis , identified from the same NGS database, from the Mayo Clinic.

It was noted that the prevalence rate of any BRAF mutation was 10%, non-V600 BRAF mutations occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Of particular clinical interest, compared with those with V600E BRAF mutations, patients harboring a non-V600 BRAF mutation were significantly younger, more frequently male, and presented with left-sided MicroSatellite-Stable (MSS) tumors. Additionally, non-V600 BRAF-mutated tumors were mostly low grade and did not often metastasize to the peritoneum. The median Overall Survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and Wild-Type BRAF metastatic CRC (60.7 vs 11.4 vs 43.0 months, respectively; P<0.001) and in multivariable analysis, non-V600 BRAF mutation was independently associated with improved Overall Survival (HR=0.18; P<0.001).

This study concluded that Non-V600 BRAF mutations in metastatic ColoRectal Cancer (CRC), which accounted for 22% of all BRAF mutations identified by NGS, is a clinically distinct subtype of CRC, with an excellent prognosis and aggressive chemotherapeutic intervention could be avoided for this group of patients. Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. Jones JC, Renfro LA, Al-Shamsi HO, et al. J Clin Oncol 2017;35: 2624-2630

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 lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%).

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than age 50 years. To understand this trend, the authors in this publication conducted a retrospective cohort study among 490,305 patients aged 20 years and older, who were diagnosed with colorectal cancer between 1974 and 2013, using data from nine oldest Surveillance, Epidemiology, and End Results (SEER) registries. The SEER program is considered the gold standard for cancer registration worldwide because of the high quality of data and is the only source for historical population-based cancer incidence in the United States. This study included people born in 1890 thru 1990. Colorectal cancer incidence trends were analyzed by 5-year age group and birth cohorts.

The authors noted variations in CRC incidence patterns by age, tumor location in the colon, calendar period, and birth cohort. The study found that in adults aged 20-39 years, after a decrease in the previous decade, colon cancer incidence rates increased by 1.0-2.4% per year since the mid-1980s thru 2013. For adults aged 40-54 years during the same period, colon cancer incidence rates increased by 0.5-1.3%. Conversely, from the mid-1980s thru 2013, colon cancer rates declined in adults aged 55 years and older. In adults younger than age 50 years, there was an increasing trend for tumors to be confined to the distal colon, with the exception of adults aged 40-49 years, among whom there was an also an increasing trend for proximal tumors.

The incidence of rectal cancer has been increasing even longer and faster than colon cancer, rising about 3.2% per year from 1974-2013 in adults aged 20-29 years and from 1980-2013 in adults aged 30-39 years. In adults aged 40 to 54, rectal cancer rates increased by 2.3% per year from the 1990s to 2013. Again, rectal cancer rates declined, in adults aged 55 years and older, from 1974-2013.

Compared with adults born around 1950, those born around 1990 had double the risk of colon cancer and quadruple the risk of rectal cancer. The increase in the incidence of CRC in young adults has been attributed to western style, high carbohydrate, high fat, low fiber diet which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking. Further, young patients are 58% more likely than older patients to be diagnosed with advanced versus localized stage CRC, due to delayed follow-up of symptoms, sometimes for years and these young adults are less likely to be screened for colon cancer, despite their symptoms.

The authors concluded that there is an increasing rate of colon and rectal cancer among young and middle-aged adults in the US and compared with adults born around 1950 when the risk was at the lowest, those born around 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer. They added that as nearly a third of rectal cancer patients are younger than age 55 years, screening initiation before age 50 years should be considered. Colorectal Cancer Incidence Patterns in the United States, 1974-2013. Siegel RL, Fedewa SA, Anderson WF, et al. J Natl Cancer Inst. 2017 Aug 1;109(8). doi: 10.1093/jnci/djw322.

SUMMARY: The FDA on July 31, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. 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 lifetime risk of developing ColoRectal Cancer is about 1 in 20 (5%).

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 therefore are susceptible to PD-1 blockade with immune checkpoint inhibitors.

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. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer.

This latest approval for OPDIVO® was based on results from the phase II CheckMate-142 trial, which is a multicenter, open label, single arm study, involving 53 patients with dMMR or MSI-H metastatic ColoRectal Cancer, who had disease progression during, after, or were intolerant to prior treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy. These 53 patients were a subset of the 74 patients who received at least one prior treatment regimen containing a Fluoropyrimidine with Oxaliplatin or Irinotecan for metastatic disease. All patients received OPDIVO® 3 mg/kg by intravenous infusion every 2 weeks until unacceptable toxicity or radiographic progression. The median age was 53 years. The Primary endpoint was Objective Response Rate (ORR) and exploratory endpoints included Safety, Progression Free Survival, Overall Survival and efficacy in biomarker-defined populations.

The Objective Response Rate as assessed by independent radiographic review committee, was 28% in the 53 patients who received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan and responses lasted 6 months or more for the 67% of the responding patients. There was 1 complete response and 14 partial responses. The ORR was 32% among the 74 patients in the overall population. These responses and Clinical Benefit was seen regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome. The most common adverse reactions related to OPDIVO® included fatigue, asthenia, rash, fever, nausea, diarrhea, musculoskeletal pain, cough and dyspnea.

The authors concluded that patients with metastatic ColoRectal Cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy and OPDIVO® demonstrated durable responses and disease control in this heavily pretreated patient group. Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142. Overman MJ, Lonardi S, Leone F, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 519).

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. Patients with ColoRectal Carcinoma are often followed up with regular CEA measurements after curative surgical resection and a rising CEA may be the first sign of CRC recurrence and warrants further investigation. Approximately 50% of the patients with early-stage disease after surgical resection will relapse with metastatic disease, during the first 3 years of follow-up. They may present with synchronous disease defined as distant metastases occurring within 6 months, and metachronous disease defined as distant metastases occuring beyond 6 months, of the primary diagnosis of CRC. These patients with oligo-metastatic disease, when detected early, may be potentially curable.

The authors in this study sought to (a) evaluate the utility of PET-CT in detecting occult disease recurrence in patients with raised CEA and (b) establish the prognostic effects of early detection of disease recurrence in patients with CRC. This retrospective analysis screened1200 patients from 2004 to 2010, with a confirmed diagnosis of CRC, who on follow up after curative therapy underwent FDG PET-CT imaging, for an elevated CEA, after normal findings on conventional investigations. Patients who had already received treatment with curative intent for synchronous or metachronous oligo-metastatic disease, including surgical resection, radiofrequency ablation (RFA), and radical chemoradiation, were also included. An elevated CEA level was defined as more than 3 ng/mL in nonsmokers and more than 5 ng/mL in smokers. A minimum of clinical and radiological follow up for 12 months or histopathological confirmation, were required, to ascertain recurrent disease. Eighty eight (N=88) patients who underwent PET-CT imaging because of any clinical indication and met the eligibility criteria, were included in the study. The mean age of patients was 66 years and 59% were male.

Recurrent disease was confirmed in 64% of the patients within the 12 months after their FDG PET-CT scan and the PET scan was able to detect the site of subtle relapse. The sensitivity of PET-CT to detect recurrence was 88% and the specificity was 88% as well. Fifty five percent (55%) of the patients with PET-CT-detected relapsed disease were deemed eligible for further curative therapy of whom 70% went on to receive potentially curative therapy. The Positive Predictive Value and Negative Predictive Value for FDG PET-CT to predict recurrence were 93% and 80% respectively.

The median Time To Progression for patients who received potentially curative therapy for the PET-CT-detected recurrence was 8.8 months versus 2.2 months for the patients not treated with curative intent. The median Overall Survival was 39.9 months for those who received potentially curative treatment versus 15.6 months for those who did not receive curative therapy. The 5-year survival rate in the curative group was 36.8% versus 6.1% in the non-curative group (P <0.001).

The authors concluded that early use of FDG PET-CT in patients with rising CEA levels is a highly sensitive and specific tool for the detection of occult ColoRectal Cancer recurrence, and in more than 50% of these patients, recurrent disease may still be amenable to curative therapy, and long-term survival can be achieved in a subgroup of this patient population. Survival Outcomes in Asymptomatic Patients With Normal Conventional Imaging but Raised Carcinoembryonic Antigen Levels in Colorectal Cancer Following Positron Emission Tomography-Computed Tomography Imaging. Khana K, Athaudaa A, Aitken K, et al. The Oncologist 2016;21:1502-1508