•  Colorectal cancer is not only the third most commonly diagnosed cancer but also the third leading cause of cancer death in men and women. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States.1

•  Activating mutations in human Kirsten rat sarcoma viral oncogene (KRAS) are detected in approximately 40 percent of metastatic colorectal cancer (mCRCs). Mutations in B-RAF murine sarcoma viral oncogene homolog B1 (BRAF) are found in 5 to 10 percent of mCRCs.2

•  The RAS-RAF-MEK-ERK signaling pathway (MAPK pathway) is a classical intracellular pathway that plays a crucial role in homeostasis of normal cell turnover, cellular proliferation, differentiation, survival, and apoptosis. KRAS mutations and BRAF mutations result in constitutive activation of the RAS-RAF-MEK-ERK pathway leading to resistance to anti-EGFR therapy.

Discussion

This very rare case of metastatic colorectal cancer with concomitant KRAS and BRAF mutations emphasizes the importance of obtaining baseline testing of KRAS and BRAF mutations as it appears that patients with coexistent mutations tend to have aggressive course of disease as evident in this patient.

This case opens the following questions:

Ø  Does Anti-EGFR therapy worsen outcomes in patients with KRAS and BRAF mutations?

CRYSTAL3 and PRIME4 are two most important randomized controlled trials that demonstrated that addition of anti-EGFR drugs to chemotherapy has detrimental outcomes in KRAS mutant mCRC. The MRC COIN trial5 showed that addition of anti-EGFR drugs to chemotherapy had detrimental outcomes in BRAF mutant mCRC. The above table shows the PFS and OS in KRAS and BRAF mutant mCRC. The above graphs show worse survival with anti-EGFR therapy when KRAS and BRAF are mutant (blue curves).

Ø  Can Vemurafenib be used in patients with BRAF mutated colorectal cancer?

An on-going clinical trial conducted by Southwest Oncology group is evaluating the role of Irinotecan and Cetuximab with or without Vemurafenib in patients with BRAF mutant mCRC (NCT02164916).

Background: Activating mutations in human Kirsten rat sarcoma viral oncogene (KRAS) are detected in approximately 40 percent of metastatic colorectal cancer (mCRCs). KRAS mutations result in constitutive activation of the RAS-RAF-ERK pathway leading to resistance to anti-EGFR therapy. B-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations are found in about 5 to 10 percent of mCRCs. BRAF mutations, most of which are V600E mutations, are associated with poor prognosis.

Case Report: A 29-year old Hispanic woman with no significant medical, family and smoking history presented to the clinic with complaints of abdominal pain, nausea, fatigue and constipation. Laboratory tests indicated the presence of microcytic hypochromic iron deficiency anemia and mild transaminitis. Imaging evaluation revealed marked hepatomegaly with multiple hepatic metastases and pelvic lymphadenopathy. Biopsy of the hepatic lesions showed adenocarcinoma positive for pan-cytokeratin, CMA5.2, villin and CDX2. She was positive for tumor markers CA 19-9, CA-125 and CEA. Upon further evaluation, she was found to have colorectal cancer positive for KRAS mutation (C 35 G>A/p. G12D) and BRAF mutation (Exon 15 codon 600). She was not considered for anti-VEGF treatment as she was found to have an active infectious fistulous communication between a uterine fibroid and the bowel wall. FOLFOX therapy was administered for 2 cycles and then discontinued, as she was deemed unresponsive to treatment based on visualization of progressive lesions and a rise in tumor marker levels. Unfortunately, her disease progressed rapidly and she expired within 3 months from the time of her first diagnosis.

Discussion: KRAS and BRAF mutations are rare enough to be considered virtually (albeit not entirely) mutually exclusive but coexistent mutations appear to be a distinct molecular and clinical subset with aggressive course of illness, which is in dire need of new treatment strategies. In the United States, Panitumumab and Cetuximab are approved for patients with wild type KRAS tumors in colon cancer. Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF, which prolongs progression-free and overall survival in melanoma patients with BRAF mutation but its use in BRAF mutated colon cancer is not well established. Our report highlights the need to obtain tissue samples from these patients for analysis and to evaluate the benefit of Vemurafenib in colorectal cancers.

Abstract

1.  Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. 2.  Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS Mutations and Individual Variation Patterns Among Patients With Metastatic

Colorectal Cancer: A Pooled Analysis of Randomized Controlled Trials. Eur J Cancer. 2015;51(13):1704-13. 3.  Van Cutsem E, Lenz HJ, Kohne CH, et al. Flourouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in

Colorectal Cancer [CRYSTAL study]. J Clin Oncol. 2015;33(7):692-700. 7.  Douillard JY, Siena S, Cassidy J, et al. Randomized Phase III Trial of Panitumumab With FOLFOX 4 Vs FOLFOX4 Alone as First-line

Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. J Clin Oncol. 2010;28(31):4697-705. 8.  Maughan TS, Adams RA, Smith CG, et al. Addition of Cetuximab to Oxaliplatin-based First Line Combination Chemotherapy for Treatment of

Advanced Colorectal Cancer: Results of The Randomised Phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103-14.

A 29-year old Hispanic woman with no significant medical, family and smoking history presented to the clinic with complaints of abdominal pain, nausea, fatigue and constipation. Laboratory tests indicated the presence of microcytic hypochromic iron deficiency anemia and mild transaminitis. Hb was 7.8 and AST/ALT/ALP were 92, 34, 144 on her first presentation to clinic. CT and PET scan showed a large mass in the distal sigmoid colon and proximal rectum with abdominal and pelvic lymphadenopathy and innumerable necrotic lesions in the liver concerning for metastasis. Biopsy of the hepatic lesions showed adenocarcinoma positive for pan-cytokeratin, CMA5.2, villin, and CDX2. Tumor markers were as follows: CA 19-9 (981), CA-125 (205) and CEA (284.3). Flexible sigmoidoscopy confirmed the necrotic mass which was present 11 cm from the anal verge and biopsies were obtained. Biopsies were positive for KRAS mutation (C 35 G>A/p. G12D) and BRAF mutation Exon 15 codon 600 at V600E (GAG). As she was found to be positive for both KRAS and BRAF, she was not considered a candidate for anti-EGFR treatment. Anti-VEGF treatment could not be considered in her case as she was found to have an active infectious fistulous communication between a uterine fibroid and the bowel wall. FOLFOX therapy was administered for 2 cycles and she tolerated it well. Further treatment was discontinued, as she was deemed unresponsive to treatment based on visualization of progressive lesions and primary tumor. Unfortunately, her disease progressed rapidly and she expired within 3 months from the time of her first diagnosis.

Are All Mutations The Same? A Rare Case Report Of Coexisting Mutually Exclusive KRAS And BRAF Mutations In A Patient With Metastatic Colon Adenocarcinoma

Anusha Vittal MBBS 1, Anup Kasi Loknath Kumar MD, MPH 2 1 Department of Internal Medicine, 2 Division of Medical Oncology,

University of Kansas Medical Center, Kansas City, KS

.

Efficacy  (in  months)  

Progression  free  survival  

Overall  Survival  

CRYSTAL  (mKRAS)  n=397  

FOLFIRI  +  Cetuximab  =  7.4  

FOLFOX  +  Panitumumab  =  7.3  

FOLFIRI  =  7.5   FOLFOX  alone  –  8.8  

PRIME  (mKRAS)  n=440  

FOLFIRI  +  Cetuximab  =  16.4  

FOLFOX  +  Panitumumab  =  15.5  

FOLFIRI  =  17.7   FOLFOX  =  19.3  

MRC  COIN  (mBRAF)  n=102    

NA   FOLFOX  +Cetuximab    =  7.2  FOLFOX  =  10  

Our  PaPent  (mKRAS  +  mBRAF)  

1  month   3  months  

Background

Case Presentation

Discussion

•  mCRC harboring concomitant KRAS + BRAF mutations is an aggressive subset which is in dire need of new therapeutic strategies.

•  Baseline testing of KRAS and BRAF mutations needs to be obtained as a new standard of care in the clinical management of mCRC patients.

•  We are currently conducting a retrospective chart review study to assess the incidence and biology of coexisting mutations in mCRC at University of Kansas.

•  mCRC with concomitant KRAS + BRAF mutations should be assigned to a separate arm in clinical trials to evaluate the role of novel therapeutics for this deadly disease.

Future Directions

References

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