Cusnir Explains the Importance of Molecular Testing in 2 Cases of mCRC

Mike Cusnir, MD

Mike Cusnir, MD

Mike Cusnir, MD, co-director of gastrointestinal malignancies, Mount Sinai Medical Center, recently discussed the cases of 2 patients with metastatic colorectal cancer (mCRC).

Case 1

February 2013

A 53-year-old Caucasian man presented to his gastroenterologist complaining of rectal bleeding and abdominal tenderness. His past medical history included hypertension, well-controlled on a beta-blocker. His mother died of breast cancer.

He underwent colonoscopy with biopsy. Pathology results confirmed poorly-differentiated adenocarcinoma. Genetic testing was positive forKRASexon 2 codon 12 mutation. A CT scan of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. His diagnosis was adenocarcinoma of the colon; staging, T4N0M1.

TARGETED ONCOLOGY:What type of molecular testing should be ordered for this patient?

Cusnir:The most important thing that one has to be cognizant of is that we're dealing with a patient who was already found to be aRAS-mutant patient. With the patient beingRAS-mutant, the usefulness of our further molecular testing has been raised to question if there is anything out there that would modify the treatment of this patient. You could argue here both ways of not pursuing any other testing, or the opposite, to proceed with an extended evaluation for future reference of other things that you might find useful in these situations. Most of the time, the one that should be most of concern isBRAF, which tends to be mutually exclusive fromKRASmutations. However, by adding an extended panel, you might find mutations likePI3KCthat some people have found useful to predict other therapies. People may find it useful to do a much more expanded molecular profile. OtherRASmutations will not make any difference whatsoever.

TARGETED ONCOLOGY:Should this patient undergo microsatellite instability (MSI) testing?

Cusnir:That is an absolute yes. On the level of MSI testing, there are several cases where patients could haveKRAS-mutant tumors that are still microsatellite unstable. Knowing that there are 2 drugs approved for the treatment of these patients, all colorectal carcinomas should be tested for MSI. The treatment options for a patient like this who is fairly young with an extremely good performance status, without major issues and knowing that their hypertension is well controlled, it's mostly going to be with antiangiogenic-based chemotherapy. The backbone of chemotherapy is a consideration of a FOLFOX [oxaliplatin, fluorouracil (5-FU), and folinic acid] or FOLFIRI [irinotecan, fluorouracil, and folinic acid] frontline regimen with most likely bevacizumab [Avastin]. Knowing that the patient has a new tumor, even with 1 of the 2 backbones to use, it's not completely well understood, so I think that one might equally choose one or the other. Maybe even considering a triplet combination of FOLFOXIRI [irinotecan, fluorouracil, folinic acid, and oxaliplatin] with a mutant tumor—it's also questioned, but it's now been investigated much more than on the TRIBE study.

The patient was started on FOLFOX and bevacizumab, therapy was well tolerated. The second follow-up scan showed a marked decrease in volume of the primary tumor, 2 of the liver lesions, and the lung lesion.

March 2014

The patient complained of intermittent shortness of breath, but continues his normal activities. Imaging showed slow but steady progression in the plural lesion.

TARGETED ONCOLOGY:What are the choices for therapy at this point?

Cusnir:This patient progressed on frontline therapy with FOLFOX/bevacizumab that lasted for quite a while, because it appears that his response was long lived, meaning more than 3 months with regional therapy. Data will support switching the backbone of chemotherapy from FOLFOX to FOLFIRI or vice versa, and continuing with the antiangiogenic treatment. Use of other antiangiogenics is the biggest question of the day here. If one could consider using ziv-aflibercept [Zaltrap] or ramucirumab, which are both approved for this indication, it is an appropriate option as well. It's not commonly done, but they are approved indications.

Bevacizumab therapy was continued; the patient was also started on FOLFIRI. Follow-up imaging showed continued regression of the lung lesion; the patient continues to tolerate therapy with management of gastrointestinal distress.

February 2017

The patient complained of abdominal fullness, nausea, and constipation. He continued to work full time, but felt sluggish. An MRI indicated diffuse metastatic disease in the peritoneum, consistent with carcinomatosis.

TARGETED ONCOLOGY:What are the therapy choices at this point?

Cusnir:The options are limited to regorafenib [Stivarga] and TAS-102 [Lonsurf].

I tend to be of the opinion that it's about looking at the toxicities at this time. We do not have a comparison study of using one agent or the other in this setting. If a patient has not had anything that has toxicity for the skin, they can consider using regorafenib; however, if the patient has been using a lot of drugs that are bone marrow toxic, you can use TAS-102 to give a break to the bone marrow. Since this patient has a mutation, there is a scientific rationale for considering using regorafenib, because it's a multikinase inhibitor. It might give better coverage and might be able to cover some of the patients who are mutant at this time. I tend to favor regorafenib in the third-line, but again, both options are perfectly appropriate.

Case 2

October 2016

A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction. Her past medical history includes arterial hypertension, well controlled on an ACE inhibitor and coronary angioplasty with stent placement 4 years ago. Her carcinoembryonic antigen was 23.3 ng/mL.

Pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 of which were metastatic. Imaging with PET/CT showed several lung lesions, 3 measuring up to 3.0 cm in size. Her mutational status wasRASandBRAFwild-type. She was microsatellite stable. Her diagnosis was high grade colorectal adenocarcinoma, stage T4N2M1.

TARGETED ONCOLOGY:What are the options for upfront therapy in this patient with unresectable, all-RASandBRAFwild-type mCRC?

Cusnir:In this type of patient, the benefit of using EGFR-directed therapy is important. That being said, maintenance therapy for patients who are getting, say, a FOLFIRI/cetuximab [Erbitux] or FOLFIRI/bevacizumab frontline regimen, is not well studied. There are some small studies from Europe and Asia of using cetuximab maintenance or switching to fluorouracil maintenance therapy in this patient; however, the data for maintenance in patients who are started on antiangiogenics is stronger. That being said, it is also important to know that the data for bevacizumab versus cetuximab in left-sided tumors is only a 4-month difference in survival. When you have a conversation with the patient about the toxicities associated with both options, a lot of the patients tend to go for bevacizumab in the frontline, even though patients with left-sided tumors who take cetuximab appear to have a 4-month improvement in survival. That is something that is important to be considered in this case.

The patient received systemic therapy with FOLFIRI plus bevacizumab. Grade 1 rash and grade 2 thrombocytopenia were managed with a dose adjustment of FOLFIRI. Follow-up imaging at 2 and 4 months showed significant responses in the lung lesions. The patient was continued on maintenance therapy with cetuximab.

August 2016

The patient complained of weight loss, nausea, and fatigue. A CT of the chest, abdomen, and pelvis showed marked progression in 2 of the lung lesions and development of new liver lesions.

TARGETED ONCOLOGY:Should she be evaluated for localized treatment of her lung and liver lesions?

Cusnir:With localized treatment of lung and liver lesions, it all depends on if they really needed it. If they have very limited disease, that is an option to go for localized therapies. However, on this case, I wouldn't add a VEGF-targeted antibody, I would say replace the chemotherapy.

TARGETED ONCOLOGY:What are the options for this patient following progression?

Cusnir:At this point, it's deciding which to try, regorafenib or TAS-102, and there is not enough data to support one over the other. In the setting of progression, regardless of wild-type or mutant tumors, it's mostly a matter of toxicity.

TARGETED ONCOLOGY:Why is proactive monitoring important for side effects and patient education?

Cusnir:We tell the patient that they need extremely close follow-up. There are several international studies where the data of doing weekly follow-ups for the first 2 or 4 weeks up to 6 weeks and then spacing it to every 2 weeks is quite important. Proactive monitoring is very important to monitor side effects and allow the patient to benefit as much as they can from the drug.

There are several database reviews that have shown that patients who have more lines of therapy have better survival. It is important to consider that if the patient has a good performance status, that they should continue to use all the different medications that are available to them instead of stopping because we don't believe much in the data of median survival when the overall hazard ratio for the drugs in the third and fourth line is close to 30% of the patients deriving benefit from the medications.