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 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable with a 5-year survival rate of 11%.

The 2019 NCCN guideline update for colon cancer has expanded the scope of personalized medicine and clinical diagnostics by incorporating biomarker testing to guide treatment. With the identification of new biomarkers and expansion of biomarker testing to guide treatment among patients with colorectal cancer, studies are underway to classify colorectal cancer (CRC) based on comprehensive gene expression profiles. The Consensus Molecular Subtypes (CMS) is one of the most robust transcriptome-based classification of colorectal cancer (CRC). The CMS subtype may influence the efficacy of chemotherapy and CMS might be a new predictive factor for the efficacy of chemotherapy against mCRCs. The CRC Subtyping Consortium (CRCSC) initiated by 15 institutions analyzed more than 30 different gene expression sets across multiple platforms and sample preparation methods and identified four different molecular subtypes, CMS1, CMS2, CMS3 and CMS4. This covers approximately 87% of all CRC cases, thus leaving approximately 13% of cases molecularly uncharacterized.

CMS1: Approximately 14 percent of all CRC are considered CMS1, of which approximately 12 percent are sporadic (non-inherited), while the remaining patients have inherited disease (Lynch Syndrome). Tumors are located in the proximal colon, have a high BRAF V600E mutation rate and are associated with impaired DNA mismatch repair (MMR). Patients in this group tend to have a lower rate of relapse and if relapse does occur, they are associated with poor outcomes (about 9 months). The 5-year survival rate for this group is about 73%.

CMS2: This is the most common CRC subtype with approximately 39% of the CRC patients belonging to this group. Majority of the tumors are located in the left colon and tumors are characterized by the initial loss of APC, a tumor suppressor gene, followed by an activating mutation in KRAS and loss of TP53. Patients in this group have higher survival rates (35 months) after relapse. The 5-year survival rate for this group is 77%, the best among the four different CRC subtypes.

CMS3: Approximately 13 percent of CRC patients belong to this group. KRAS mutations are most frequently found in this patient group (68%) and approximately 3% of patients in this group overexpress HER2. Patients in this group have the second highest survival rates, with a 5-year survival rate of 75%.

CMS4: These tumors are characterized by MSS (MicroSatellite Stable) with frequent mutation of genes such as APC, KRAS, PIK3CA, and TP53. Patients in this group often have poor prognosis as they are diagnosed at advanced stages. They have little or no benefit from systemic adjuvant therapy and those with metastatic disease are often resistant to EGFR inhibitors, independent of KRAS mutation status. They have the worst 5-year Overall Survival (62%) of any molecular subtype.

The following are the key 2019 NCCN guideline updates 

KRAS, NRAS and BRAF Mutation Testing

All patients with metastatic colorectal cancer should have tumor tissue genotyped for KRAS, NRAS and BRAF mutations individually or as a part of Next Generation Sequencing (NGS) panel

MicroSatellite Instability (MSI) or MisMatch Repair (MMR) Testing

1) The presence of BRAF V600E mutation in the setting of absence of MLH1 would preclude the diagnosis of Lynch Syndrome in a majority of cases. However, approximately 1% of cancers with BRAF V600E mutation and loss of MLH-1 are Lynch Syndrome and therefore, caution should be exercised, in excluding patients with a strong family history from germline screening in the case of BRAF V600E mutations

2) ImmunoHistoChemistry (IHC) refers to staining of tumor tissue for protein expression of the four mismatch repair MMR genes, MLH1, MSH2, MSH6, and PMS2, known to be mutated in Lynch Syndrome. A normal IHC test implies that all 4 MMR proteins are normally expressed or retained. An abnormal or positive IHC test implies loss or absence of expression of one or more of the 4 MMR proteins. When IHC is reported as positive, caution should be exercised to ensure that positive IHC refers to absence of mismatch expression and not presence of expression. Loss of expression by IHC in any of the MMR genes should then be followed up with genetic testing. Abnormal MLH1 on IHC should be followed by tumor testing for BRAF V600E mutation. The presence of BRAF V600 E mutation is consistent with sporadic cancer.

mFOLFOXIRI + EGFR

mFOLFOXIRI with EGFR inhibitor VECTIBIX® (Panitumumab) or ERBITUX® (Cetuximab) was added as a treatment option for unresectable stage IV mCRC that are left-sided and are KRAS/NRAS/BRAF wild-type.

mFOLFOX + EGFR

The combination regimen FOLFOX + VECTIBIX® or ERBITUX® was added for KRAS/NRAS/BRAF wild-type tumors.

Immunotherapy

Patients with advanced or metastatic CRC who are not appropriate candidates for intensive therapy may be offered OPDIVO® (Nivolumab) or KEYTRUDA® (Pembrolizumab), as a single agent or a combination of OPDIVO® and YERVOY® (Ipilimumab), only for tumors that are MMR deficient and MSI High (Category 2B). These same immunotherapy options are also listed in the guidelines as second and third-line options for MMR deficient and MSI High patients.

NTRK Gene Fusion

Tumors should be tested for Neurotrophic Receptor Tyrosine Kinase (NTRK) gene fusion, and VITRAKVI® (Larotrectinib) is now a second-line treatment option for patients with metastatic CRC that is NTRK gene fusion positive.

BRAF and MEK

BRAF wild-type was added as an indication for treatment, where KRAS and NRAS wild-type are noted. Combination therapies added to the guidelines as second-line options include

1) TAFINLAR® (Dabrafenib) targeting BRAF plus MEKINIST® (Trametinib) targeting MEK along with ERBITUX® or VECTIBIX® which are EGFR targeted monoclonal antibodies

2) BRAFTOVI® (Encorafenib) targeting BRAF plus MEKTOVI® (Binimetinib) targeting MEK along with ERBITUX® or VECTIBIX®.

NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. Messersmith WA. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

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 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) Colon Cancer, has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with Stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

This ASCO Clinical Practice Guideline was based on the IDEA Collaboration, which is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be non-inferior. Approximately, 40% of patients received CAPOX regimen and 60% received FOLFOX regimen. The Primary endpoint was Disease Free Survival (DFS).

In an exploratory subgroup analyses by risk of recurrence within the high-risk group defined in the IDEA Collaboration (T4 – tumor invades through the visceral peritoneum including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum or tumor directly invades or adheres to other adjacent organs or structures and/or N2 – metastasis in 4 or more regional lymph nodes), superior DFS was found with 6 months versus 3 months duration of ELOXATIN® based adjuvant chemotherapy. In the low-risk group however, (T1-tumor invades submucosa, T2-tumor invades muscularis propria, or T3-tumor invades through the muscularis propria into the pericolorectal tissues and N1-metastasis in 1-3 regional lymph nodes), DFS was noninferior with 3 months versus 6 months duration of adjuvant chemotherapy.

In prespecified subgroup analysis by type of ELOXATIN®-based chemotherapy, 3 months of treatment was non-inferior to 6 months for patients treated with CAPOX regimen. However, 3 months of treatment was inferior to 6 months, for patients treated with FOLFOX regimen. It has been hypothesized that the protracted delivery of a Fluoropyrimidine with CAPOX might have been more effective than the twice-monthly 5-FUinfusions with FOLFOX as an adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for CAPOX/XELOX, respectively).

It was concluded from this study that a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with Stage III Colon Cancer, taking into consideration choice of treatment regimen and duration of therapy. In patients treated with adjuvant CAPOX/XELOX regimen, 3 months of therapy was as effective as 6 months, particularly in the low risk subgroup. In patients treated with FOLFOX, 6 months of adjuvant therapy compared to 3 months, resulted in a higher rate of Disease Free Survival, particularly in the high-risk subgroup.

Guideline Question: What is the optimal duration (3 months vs 6 months) of ELOXATIN®-based chemotherapy for patients with completely resected Stage III Colon Cancer?

Target Population: Patients with completely resected Stage III Colon Cancer. Target Audience: Medical oncologists, general surgeons, colorectal surgeons, surgical oncologists, and oncology Advanced Practice Providers who treat patients with Colon Cancer.

Methods: A multidisciplinary Expert Panel which included clinicians with expertise in colorectal surgery and medical oncology as well as a patient representative and an ASCO guidelines health research expert, was convened to develop clinical practice guideline recommendations, based on a systematic review of the medical literature from April 2004 to August 2018, for Phase III randomized clinical trials (RCTs) that included a comparison of two or more durations of treatment with FOLFOX or CAPOX chemotherapy.

Recommendations for patients with Stage III resected Colon Cancer who are being offered treatment with ELOXATIN®-based chemotherapy.

Recommendation 1: For patients with High-risk (T4 and/or N2) Stage III resected Colon Cancer, adjuvant ELOXATIN®-based chemotherapy should be offered for a duration of 6 months.

Recommendation 2: For patients with Low-risk (T1, T2, or T3 and N1) Stage III resected Colon Cancer, adjuvant ELOXATIN®-based chemotherapy may be offered for a duration of 3 months or 6 months, after a discussion with the patient of the potential benefits and risks of harm associated with the options for treatment duration.

Recommendation 3: A shared decision-making approach should be used for duration of ELOXATIN®-based chemotherapy for patients with Stage III resected Colon Cancer, taking into account a patient’s tumor characteristics, completeness of surgical resection, number of lymph nodes examined, comorbidities, functional status, performance status, values and preferences, age at diagnosis, life expectancy, potential years at risk for long-term sequelae of treatment, and including a discussion of the potential for benefit and risks of harm associated with treatment duration.

Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline.Lieu C, Kennedy EB, Bergsland E, J Clin Oncol. 2019;37:1436-1447.

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 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

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 50 years of age, according to data in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Based on these findings, the American Cancer Society in 2018 updated its guidelines to include a “qualified recommendation” to begin CRC screening at the age of 45 yrs. The US Preventive Services Task Force (USPSTF) and other major US organizations have however not yet changed their recommendations. 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.

The authors in this publication performed a retrospective study examining the National Cancer Data Base (NCDB) registry to determine whether the trends seen through 2013, as published from SEER program had continued to worsen through 2015 (the most recent available data from the NCDB). The National Cancer Data Base is one of the largest cancer registries in the world and includes more than 70% of newly diagnosed cancer cases in the United States and more than 34 million historical records. The researchers also examined available demographic and socioeconomic factors to determine whether they were related to CRC in young adults and further compared clinical characteristics of CRC tumors among age groups, to determine whether younger patients had differences in clinical presentation. A total of 1,185,763 cases were included in the study of whom 130,165 patients were diagnosed at an age younger than 50 yrs and 1,055,598 patients were diagnosed at the age of 50 yrs or older. The proportion of patients diagnosed before the age of 50 yrs was chosen as the Primary endpoint, as most current guidelines recommend screening starting at an age of 50 yrs.

The proportion of the total number of patients diagnosed with CRC under the age of 50 yrs rose from 10% in 2004 to 12.2% in 2015 (P<0.0001). Younger adults presented with more advanced stage of disease (Stage III/IV) than those 50 yrs or older (51.6% versus 40.0% respectively). When racial and ethnic groups were stratified by sex, among men with a diagnosis of CRC before age 50, non‐Hispanic whites showed a proportional increase in diagnosis (P<0.0001), whereas among women, both Hispanic whites (P<0.05) and non‐Hispanic whites (P<0.001) had increases in the proportion of CRC diagnosed before age 50. The rates of CRC diagnosis in young adults increased over time, regardless of income level (P<0.001).The highest proportion of young adult CRC diagnoses occurred in the highest income group. The proportion of CRC cases diagnosed in younger individuals rose in urban areas (P<0.001), but not in rural areas.

It was concluded that based on this study, that the proportion of individuals diagnosed with CRC at an age younger than 50 years, has continued to increase over the past decade in the US. Younger adults also present with more advanced disease and Health Care Providers should be mindful of these data, when screening guidelines are discussed with patients. This study however does not capture oncogenic mutations or tumor laterality, which are known to affect the prognosis. The authors pointed out that the National Cancer Data Base which provided the patient information for this study currently captures laterality only for paired organs. Recent trends in the age at diagnosis of colorectal cancer in the US National Cancer Data Base, 2004‐2015. Virostko J, Capasso A, Yankeelov TE, et al. First published: 22 July 2019. https://doi.org/10.1002/cncr.32347

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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. STIVARGA® (Regorafenib), is an oral multi-kinase inhibitor and inhibits multiple kinases including VEGF1, VEGF2, VEGF3, PDGFR, FGFR involved in tumor angiogenesis and KIT, RET, RAF-1, BRAF involved in oncogenesis. STIVARGA® is approved by the FDA for the treatment of patients with metastatic CRC, who have progressed on 5FU, ELOXATIN® (Oxaliplatin), CAMPTOSAR® (Irinotecan), anti-VEGF and anti-EGFR therapies, at a dose of 160 mg orally, once daily for the first 21 days of each 28-day cycle. The approval was based on a phase III trial in which patients receiving STIVARGA® had a statistically significant improvement in the Overall Survival (OS) and Progression Free Survival (PFS), compared to placebo.

The starting dose of STIVARGA® has been an obstacle and toxicities such as Palmar-Plantar Erythrodysesthesia Syndrome (PPES) commonly occurring during the first 2 weeks, as well as fatigue and hypertension have limited its use. Various dosing schedules have been implemented into clinical practice, despite the absence of reliable supportive data. There is therefore a need to optimize the dose of STIVARGA® in patients with refractory mCRC to maintain efficacy, while improving the tolerability profile. CORRELATE study looked at the data from the real-world setting of refractory mCRC regarding the dosing of STIVARGA® and safety, whereas the ReDos study evaluated a dose-escalation strategy, starting with a lower dose of STIVARGA®.

CORRELATE is a prospective, international observational study conducted in 13 countries to evaluate the use STIVARGA® in a real-world setting, based on safety and efficacy. The primary objective of this study was to assess safety. This final analysis describes the real-world dosing of STIVARGA® in mCRC.

Of the 1037 patients included in this study, 57% started treatment at 160 mg, 30% at 120 mg, and 13% at 80 mg or less. The mean dose administered was 75% of the approved dose. The median patient age was 65 years and majority of the patients had an ECOG performance status (PS) of 0-1 (87%). Dose reductions were more frequent in the 160 versus 120 mg group and treatment modifications were most commonly due to treatment related adverse events (66%). Most treatment discontinuations (49%) were due to radiologic disease progression, whereas 19% were due to STIVARGA® related adverse events. Treatment related adverse events of any grade occurred in 95% of patients, and 80% were attributed to STIVARGA®. Median overall survival (OS) was 7.6 months and the estimated 1-year OS was 34%.

It was concluded from this real-world, observational study that the starting dose of STIVARGA® for nearly half of patients was less than 160 mg/day and the common treatment related adverse events were generally consistent with the known safety profile of STIVARGA® in mCRC. Despite the dose modifications of STIVARGA®, there was no significant impact on its efficacy in terms of the median OS and median PFS.

ReDOS is a randomized phase II study in which STIVARGA® dose-escalation strategy beginning at a lower starting dose of 80 mg daily and ending at 160 mg daily was compared with the standard dose, in patients with refractory mCRC. In this dose escalation study, patients in Arm A (N=54) received STIVARGA® 80 mg daily, with weekly dose escalation up to 160 mg daily, if no significant drug-related toxicities were experienced, where as in Arm B (N=62), patients received the standard dose of STIVARGA® 160 mg daily, for 21 days of a 28-day cycle. The median age was 61 years and both treatment groups were well balanced. The Primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd cycle if there was no progression.

The study met its primary endpoint with 43% of patients on Arm A initiating the 3rd cycle versus only 25% of patients on Arm B (P=0.028). The median Overall Survival (OS) was improved in Arm A versus Arm B (9 months versus 5.9 months ; P=0.094). The median Progression Free Survival (PFS) was 2.5 months for Arm A and 2 months for Arm B (P=0.55). Overall grade 3 and 4 toxicities were lower on Arm A versus Arm B and multiple Quality Of Life parameters were improved in Arm A versus Arm B, at week 2 of the first cycle.

It was concluded that weekly dose escalation of STIVARGA® from 80 mg to 160 mg daily was superior to a starting dose of 160 mg daily. Based on this study, the NCCN has updated its ColoRectal Cancer (CRC) guidelines, recommending a weekly STIVARGA® dose-escalation strategy beginning at 80 mg and ending at 160 mg, for previously treated patients with metastatic ColoRectal Cancer.

Real-world dosing of regorafenib (REG) in metastatic colorectal cancer (mCRC): final results from the prospective, observational CORRELATE study. O'Connor JM, Ducreux M, Petersen LN, et al. Ann Oncol. 2018;29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)-an ACCRU Network study. Bekaii-Saab TS, Ou FS, Anderson DM, et al. J Clin Oncol. 2018;36(suppl 4S; abstr 611)

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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Advanced colon cancer is often incurable and 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 also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. 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 V600E mutations and BRAF V600E 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 V600E 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® is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). In a phase II SWOG trial (SWOG 1406), the addition of ZELBORAF® to the combination of CAMPTOSAR® (Irinotecan) 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.

Unlike primary colorectal cancer, the association of BRAF V600E and non-V600E mutations with survival and tumor recurrence after resection of ColoRectal Liver Metastases (CRLM), has remained unclear. This present study was conducted to investigate the prognostic association of BRAF mutations with survival and recurrence independently, and to understand how BRAF mutations compared with other prognostic determinants, such as KRAS mutations. This cohort study enrolled 853 patients with colorectal tumors and liver metastases, of whom 849 patients were evaluable and included in the study analyses. All patients underwent resection of their ColoRectal Liver Metastases with a curative intent from January 1, 2000, through December 31, 2016, at institutions participating in the International Genetic Consortium for Colorectal Liver Metastasis and had available data on BRAF and KRAS mutational status. The median age was 60 years, and 60% were male. The main outcomes and measures were the association of BRAF V600E and non-V600E mutations with Disease Free Survival (DFS) and Overall Survival (OS).

Forty three patients (5.1%) had a mutated BRAF (V600E and non-V600E) /wild-type KRAS genotype, 480 patients (56.5%) had wild-type BRAF/wild-type KRAS genotype; and 326 patients (38.4%) had a wild-type BRAF/mutated KRAS genotype. Compared with the wild-type BRAF/wild-type KRAS genotype group, patients with a mutated BRAF/wild-type KRAS genotype more frequently were female (62.8% vs 35.2%) and 65 years or older (51.2% vs 36.9%), had right-sided primary tumors (62.8% vs 17.4%), and presented with a metachronous liver metastasis (64.3% vs 46.8%). The median follow up was 28.3 months.

On multivariable analysis, the presence of BRAF V600E but not non-V600E mutation was associated with significantly poor Overall Survival (HR=2.76; P<0.001) and Disease Free Survival (HR=2.04; P=0.002). Compared with KRAS mutation, the BRAF V600E mutation had a stronger association with OS and DFS than the KRAS mutations.

It was concluded that the presence of BRAF V600E mutation was associated with worse prognosis and increased risk of recurrence, and BRAF V600E mutation was not only a stronger prognostic factor than KRAS but also was the strongest prognostic determinant in the overall cohort. It remains to be seen if BRAF V600E mutated metastatic colorectal tumors would have better outcomes with targeted triplet combination therapies such as ZELBORAF® CAMPTOSAR® and ERBITUX® or TAFINLAR® (Dabrafenib-BRAF inhibitor), MEKINIST® (Trametinib-MEK inhibitor) and VECTIBIX®. Association of BRAF Mutations With Survival and Recurrence in Surgically Treated Patients With Metastatic Colorectal Liver Cancer. Margonis, GA, Buettner, S, Andreatos, N, et al. JAMA Surg. 2018;153(7):e180996. doi:10.1001/jamasurg.2018.0996

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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Advanced colon cancer is often incurable and 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 also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents.

MicroRNAs (MiRNA) are small non-coding RNA molecules that play a key role in the regulation of intracellular processes through post-transcriptional regulation of gene expression. It has been shown that MicroRNAs controlling expression of oncogenes and tumor suppressor genes are frequently deregulated in cancer cells. One MiRNA which is frequently deregulated in a variety of cancers is MiR-31, which is frequently overexpressed in colorectal cancer, with high expression correlating with advanced disease. A mature sequence of MiR-31, MiR-31-3p, has been shown to predict outcomes among for colorectal cancer patients treated with anti-EGFR therapy such as ERBITUX® and VECTIBIX®.

FIRE-3 is an open-label, randomized Phase III trial in which FOLFIRI plus ERBITUX® was compared with FOLFIRI plus AVASTIN®, as first line treatment in patients with metastatic ColoRectal Cancer (CRC). This study suggested that patients with KRAS exon 2 wild-type metastatic CRC had a longer Overall Survival (OS) when treated with FOLFIRI plus ERBITUX® compared with FOLFIRI plus AVASTIN®.

Based on the premise that MiR-31-3p expression has been shown to be associated with response to anti-EGFR therapy, in previously published studies, the authors investigated the predictive role of this biomarker in the FIRE-3 study patient population, in its ability to differentiate outcomes between patients receiving anti-EGFR and anti-VEGF therapy. In this study, MiR-31-3p expression was measured in primary tumors obtained from 340 RAS wild-type mCRC patients enrolled in the FIRE-3 Trial. The study population included 164 patients randomized to receive FOLFIRI plus ERBITUX® and 176 patients to FOLFIRI plus AVASTIN®. Patients were divided into subgroups, defined by Low or High MiR-31-3p expression.

It was noted that patients with Low MiR-31-3p expression benefited from ERBITUX® combination compared to AVASTIN® for PFS (HR=0.74;P=0.05), OS (HR=0.61;P<0.01) and Objective Response Rate (P<0.01). There was however no difference in outcomes among High MiR-31-3p expressors between the two treatment groups.

It was concluded that MiR-31-3p expression level is a validated predictive biomarker of anti EGFR therapy efficacy for RAS wild-type mCRC patients, and can enable clinicians to identify patients who would benefit from first-line anti-EGFR treatment. MiRNAs are well preserved in Formalin-Fixed Paraffin-Embedded (FFPE) tissues and MiR-31- 3p expression levels can be measured using RT qPCR. Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer. Laurent-Puig P, Grisoni ML, Heinemann V, et al. Clin Cancer Res. 2018 Aug 14. pii: clincanres.1324.2018. doi: 10.1158/1078-0432.CCR-18-1324. [Epub ahead of print]