Diagnosis of Quadruple Wild-Type Metastatic CRC


Michael A. Morse, MD:This is a man with metastatic colon cancer. It originated in the sigmoid colon. The molecular analysis showed that the tumor was wild-type forKRAS,RAS,BRAF, andPIK3CA—the so-called quadruple wild-type tumor.

The first consideration we have for people like this is whether their disease might potentially be resectable. In this case, the disease seems to be too widespread. Certainly, we would have a multidisciplinary evaluation to confirm that impression, but the expectation is that we would consider him unresectable. Therefore, he would be a candidate for palliative systemic therapy.

It’s really critical that people have phenotyping performed at the presentation of metastatic disease. Numerous studies have confirmed thatKRASmutational status is an indicator of the inability to respond to EGFR-targeted therapy. But beyond that, we now know that extendedKRASmutational analysis andNRASmutational analysis are also very important, as they are predictors of lack of response to anti-EGFR targeted therapy. Moreover, some very interesting data—from a large analysis aggregating patients from multiple sites who had been treated previously with anti-EGFR targeted therapy—suggest that the highest response rates are going to be seen in people who have the so-called quadruple wild-type—wild-type forKRAS,NRAS,BRAF, andPIK3CA.

When considering a patient for frontline therapy of metastatic colon cancer, we, of course, consider the genotyping information. We also have a discussion about what the goals are. In this case, we didn’t think the person would be a surgical candidate. But if perhaps they were borderline resectable, we would have to consider our ability to get a greater depth of response, for example. In somebody who the therapy is considered more life prolonging as opposed to intended to get to a surgical resection, then we’re really thinking about that continuum of care. What lines of therapy is the person going to be eligible for, what therapies will they be able to have in those different lines, what considerations do they have in terms of quality of life and toxicities? Do they have other comorbidities that may affect what drugs they can actually receive?

After a discussion of their goals and their comorbidities, and considering all the range of chemotherapy drugs and targeted therapies that would be available for them, we make a decision to proceed. Bevacizumab would be one of the targeted therapies that they could receive in conjunction with either a FOLFOX- or a FOLFIRI-based regimen. In this patient, who’s wild-type forRAS,KRAS,andNRAS, cetuximab or panitumumab with systemic chemotherapy would also be an option.

Recent data from large analyses suggest that tumors that are left-sided have a much better prognosis than right-sided tumors. We also know that there’s a predictive value of sidedness of the tumor. Patients with right-sided tumors do not respond well and, in fact, have lower survivals when treated with anti-EGFR targeted therapy than when treated with bevacizumab in conjunction with systemic chemotherapy. Conversely, the same analyses suggest that there could be a greater survival for patients treated with anti-EGFR targeted therapy if they have left-sided tumors compared with patients treated with bevacizumab. However, these analyses are retrospective, and at this point, it has not affected NCCN guidelines. NCCN guidelines would recommend not using anti-EGFR targeted therapy for right-sided tumors. However, NCCN guidelines allow for the use of either anti-EGFR targeted therapy or bevacizumab along with systemic chemotherapy for left-sided tumors.

One of the considerations I suggested before, when we were talking with a patient about what type of therapy to use, is comorbidities, but in fact, age can be an important factor as well. Now what defines elderly has really changed over the years. Many studies used to use the age of 65 as a cutoff for elderly. Many studies are now looking at the age of 70 or even 75 as the cutoff. Throughout all those analyses, elderly patients benefit just as much as younger patients do from these multi-agent therapies, whether it’s bevacizumab/chemotherapy or cetuximab or panitumumab with systemic chemotherapy in the metastatic setting. However, as patients reach those extremes of age—older than 75, for example—there is a greater toxicity rate for people receiving multi-agent therapies.

For FOLFIRI/cetuximab in elderly patients receiving first-line metastatic colorectal cancer therapy, there was a subsequent analysis of the CAPRI-GOIM trial, in which patients received first-line FOLFIRI with cetuximab and then were randomized to FOLFOX with cetuximab versus FOLFOX alone in the second line. When the analysis was restricted to the first-line use of FOLFIRI plus cetuximab in elderly patients, it was observed that they received the same benefit as younger patients did. However, in patients older than 75 receiving the frontline therapy, there was a trend toward increased toxicity.

Transcript edited for clarity.

October 2014

  • A 69-year old Caucasian male presented with severe left lower quadrant pain
    • He sought medical treatment after experiencing bloody diarrhea
    • PMH was remarkable for hypertension that was being managed with telmisartan
    • He was active and could perform his daily activities without restrictions or assistance
  • Laboratory evaluation was remarkable for Hb 11.3 and CEA 6.5 ng/mL
  • Colonoscopy revealed a fungating mass in the sigmoid colon which was biopsied
    • Pathological findings: invasive poorly differentiated adenocarcinoma
    • Molecular testing on the primary tumor was requested; no mutations were noted in KRAS, NRAS, BRAF, PIK3CA (quadruple wild type) and the tumor was microsatellite stable (MSS)
  • Chest, abdominal, and pelvic CT scan showed small bilateral lung nodules, a 3-cm mass in the right lobe of the liver, and a mass in the sigmoid colon measuring 10 cm
  • Diagnosis, unresectable metastatic colorectal cancer
  • Treatment was initiated with FOLFIRI + cetuximab and he appeared to respond well
  • CT scans at 3 and 6 months showed decreased size of liver and lung nodules

August 2015

  • The patient complained of increased fatigue, and reported needing frequent breaks while performing daily activities
  • CT scan showed increased size of the liver nodule (to 4 cm) and the appearance of 4 new small liver lesions (<2 cm)
  • He began therapy with FOLFOX + bevacizumab

March 2016

  • The patient complained of severe fatigue
  • CT scan revealed progressive disease with no improvement in the primary and metastatic lesion size and/or number
    • A new pulmonary nodule was seen in the right lung
  • He was then started on trifluridine/tipiracil
  • PET/CT at 3 months showed stable disease
  • At 6-months, he reported less fatigue and some improvement in performing daily tasks
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