Greg Kennelty

A small subset of patients with metastatic colorectal cancer (mCRC) have hotspot mutations in the NRAS gene, which are now being identified by extending RAS genotyping in routine clinical practice.

Maria Ignez Braghiroli, M.D., and her colleagues recently published the results of a study in which the investigators sought to identify the clinical and molecular characteristics of patients with NRAS-mutated mCRC. These findings were presented at the 2016 ESMO Congress.

-mutant mCRC is an aggressive subset of CRC, with worse overall survival rates than that of patients with 

The researchers also found that NRAS mutations define a clinically distinct subgroup of mCRC with increased left-sided colon primary tumors.

Can you tell us about clinical characteristics of patients with mCRC harboring 

 mutations. How would that have affected the results?

What would you say the current treatment paradigm is for NRAS-mutant metastatic colorectal cancer?

How much would you say mutation status affects the individual treatment of patients with colorectal cancer?

, Braghiroli, medical oncologist, Instituto do Câncer do Estado de São Paulo, discusses the current treatment paradigm for these patients and the need for more individualized treatment approaches in this setting.

We've been trying to molecularly characterize the type of tumors, and possibly try to individualize treatment. What we did is we selected all the colorectal cancer patients that were found to have 

 mutations from 2008 to 2015 that were treated at Memorial Sloan Kettering. We found a total of 87 patients, and we had to exclude three patients because they had concurrent 

 mutations and we wanted the patients with 

 mutations only. Then we compared this population in terms of clinical characteristics, molecular characteristics, and outcomes to treatment in the population with 

We don't really know, and that's why we excluded only three that had both the 

 mutations. That's why we didn't include them in the 

Basically, we know that anti-EGFR medications don't work for 

-mutant patients. These are the smaller proportion of patients with colorectal cancer, around 3 percent to 7 percent. That's why we don't really know what happens to this specific subtype of 

 mutation patients, and that is why we were looking into it. 

-mutated patients, we know that they do not respond to the anti-EGFR mutations. In general, we know that maybe 

-mutated patients have a much worse prognosis, and the studies currently focused on BRAF inhibitors or MEK inhibitors, or a combination of BRAF, MEK, and anti-EGFR inhibitors in these patients. That is actually being performed at Memorial Sloan Kettering also. A small subtype of patients actually have an amplification of HER2, for example, and they might benefit from anti-HER2 treatment.

Are there any ongoing or planned studies in this space that you are particularly excited about?

What do you hope to see in the next five or 10 years in the treatment of colorectal cancer?

There is also a sub-population that has its microsatellite stability, and maybe this population benefits from immunotherapy. So we are tending to find a small, specific subtypes of tumors, and then individualize their treatment in this way.

There are many studies in immunotherapy. I think this is very interesting, and so far for the sporadic type of colorectal cancer, we seem to not have very good results, so I think studies focusing on that will be very interesting.

Immunotherapy is one thing. I think we might understand left or right sided, and if this is really important for patients and if that has any implication for treatment. Hopefully, we'll have newer medications with more consistent improvement in survival, and maybe earlier detection via colonoscopy. It's not an easy procedure to perform for the patients, and there have been ongoing studies on fecal identification of tumor cells. That, or maybe blood identification of tumor cells to try to find them earlier.

There has been some evidence that patients with right-sided tumors may have a worse prognosis than patients with left-sided tumors. In our population with 

-mutated patients, the patients did worse than all 

 wild-type tumors, but interestingly, they had more left-sided tumors than right-sided tumors. This is still a matter of research.

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CURE spoke with Maria Ignez Braghiroli, M.D. about the need for individualized treatment for patients with NRAS-mutant metastatic colorectal cancer.

Individualized Treatment Is Needed for mCRC Subset

Treatment for diffuse gliomas and embryonal tumors, among other cancer types, have become clearer thanks to the World Health Organization’s (WHO) recently revised tumor classifications.

Can you tell use a little about the changes in WHO classifications?

What should the oncology community be aware of with this change in classification?

So you mentioned that it could change pathology. What is being done with the pathology?

, Arie Perry, M.D., chief of neuropathology at UCSF in San Francisco, California, discusses what oncologists should be aware of when diagnosing patients after these reclassifications, how it could change pathology, as well as a discussion on hereditary tumors.

The biggest classification changes are occurring in the diffuse gliomas, which is a big category mostly in adults, and embryonal tumors, which is mainly occurring in pediatric patients.

There are some new groups that are more accurately defined by molecular criteria and that if their pathologists are not doing the assays required to make those distinctions they probably need to have a chat with them or make sure that they send it out to laboratories where they are able to do that. It has prognostic significance and in some cases, will probably change the management of the patient depending on the molecular results that are obtained.

Yes, I think you know a lot of it is prognostic, so it may not necessarily change the therapeutic approach, but in some cases, if it’s a dramatic change in terms of expected survival, for example, it may impact how they approach the management of the patient. In the embryonal tumors, the pediatric cases in particular, I think there’s some really dramatic shifts in terms of either lesser aggressive therapies or more aggressive therapies depending on some of the findings.

Can you talk a little more about the hereditary tumors?

Initially, in some of those patients, especially in the pediatric cases, there are actually germline mutations that we identify so it actually has implication for the entire family, in terms of hereditary tumor syndromes. So other family members may also be at increased risk of developing certain tumor types. 

In medulloblastoma, for example, there are several tumor predisposition syndromes that are associated with some of the youngest patients that get those. One is called Gorlin syndrome, and the patients may get some other things like skin cancers or basal cell carcinomas. It also may impact whether or not they’re able to get radiation therapy, because actually it’s contraindicated in many of those patients. If you give radiation, a lot of times they’ll get skin tumors where the radiation is given.

What should we be looking for in the future with the how how tumors are classified, and what it means?

There’s another one called Li—Fraumeni syndrome that is due to p53 mutations, and other family members may be predisposed to get colon cancer, or breast cancer, or sarcomas, which are malignancies in the soft tissues in the bodies.

I think more and more we’re adding genetics into our classification scheme and probably more and more in the future we’ll also be using genomics and rather than looking at one gene at a time, or one biomarker at a time, we’ll actually be looking at the entire genome or at least cancer-associated genes within the genome. We’re already starting to do that, especially within the pediatric cases, but a subset of the adult cases as well, and so sometimes we’ll find mutations or genetic alterations that aren’t necessarily reported in that tumor type, but for which there are targeted therapies, so it may shift the way that the oncologists then decided to treat that patient.

What does the multidisciplinary approach look like at the tumor board?

I think the takeaway is that things are changing in a good way in terms of it becoming a little more complicated and more technical. But it used to be somewhat subjective and there were differences between one pathologist diagnosis and another, and I think the more we define things objectively with molecular markers, the less that’s going to occur and the more confidence the oncologists will have that the diagnosis is accurate, and more importantly perhaps will guide the way they treat individual patients, so it won’t necessarily be that everyone with the identical diagnosis will be treated the same way because there may be other differences in the molecular makeup of that tumor.

It’s the same way it has been for many years, although you know everyone’s area is becoming more complicated. I think it’s even more important that we get together once a week at least to go over patients and the intricacies of the pathology, the diagnosis, changes in radiology, what protocols may have just opened up, what’s available for certain patients, what molecular studies have shown us that may be expected or unexpected in that particular patient and then what’s the best approach for this patient going forward.

The World Health Organization (WHO) reclassified some types of brain cancers, giving a clearer outline on how to treat them.

Discussing the World Health Organization's New Brain Tumor Classification

Abraxane (nab-paclitaxel) is more beneficial than Taxol (paclitaxel) in some patients with breast cancer, as seen in the GeparSepto trial, says Sibylle Loibl, M.D., Ph.D.

Can you tell us a little about the subanalysis of the GeparSepto trial?

, Loibl, co-chair of the German Breast Group (GBG) and associate professor at the University of Frankfurt, discusses the most recent subanalysis of the GeparSepto trial, how the drugs match up in terms of toxicities, and a separate set of data looking at patients with breast cancer who are also pregnant.

The GeparSepto study was investigating if the exchange of Abraxane instead of paclitaxel followed in both arms by Ellence (epirubicin) would lead to an increased pathological complete remission (PCR) rate. This could be demonstrated overall, but we were curious to see how that would play out in the subgroups of luminal patients, triple negative breast cancer patients and HER2-positive with or without hormone receptor (HR) expression. The patients with HER2-positive disease received, in an addition to the chemotherapy, Perjeta (pertuzumab) plus Herceptin (trastuzumab) from the very beginning for the whole 24 weeks and continued afterward with Herceptin for up to one year.

We have seen that in the HER2-positive cohort, the PCR rate was much higher. We achieved a PCR rate of almost 75 percent in the HR-negative HER2-positive cohort. There was a difference in favor of Abraxane, but it was not statistically significant. In that group, the HER2 treatment is probably more important than the chemotherapy schedule. What we also found, and this has already ben seen in previous studies, is that the definition of the PCR is more important in the HER2-positive cohort than the triple negative cohort.

Are there any next steps or other analyses of this trial that are important?

The second results were about the toxicity, because there have not been so many data in the neoadjuvant setting using the two antibodies. In fact, this is the largest cohort using the two antibodies in the neoadjuvant setting and using 24 chemotherapy regimen. In TRYPHAENA, the chemotherapy was 18 weeks. We found the PCR rates were comparable to that of the TRYPHAENA trial when Perjeta was added to Herceptin, and the toxicity was also comparable to that. Especially the rate of diarrhea is to be noted, so up to 10 percent of the patients had greater than grade 2 diarrhea, which seems to be noteworthy.

We're currently conducting the rate of peripheral sensory neuropathy, and how that has evolved after patients have completed their treatment. We have seen a higher rate with peripheral sensory neuropathy with paclitaxel compared to Abraxane, but we can also see that the neuropathy is decreasing around one year after the treatment, and the rate then of grades 2 and higher is equivalent between paclitaxel and Abraxane. Grade 3 and 4 is a little more tricky because the neuropathy stays a little longer.

What do you really want the oncology community to take away from this analysis?

Do you think there will be a point where we combine Abraxane with other agents?

Can you tell us a little about your collection of data from pregnant patients with breast cancer?

At the moment the neuropathy fades away. There have been several studies investigating ameliorating treatment and supportive treatment, but so far neither has really been proven to be helpful to prevent or treat it.

What we have seen in the GeparSepto study is the greatest benefit of using Abraxane instead of paclitaxel was actually in the triple negative cohort, where we could almost double the PCR rate. This is a very important message because these are the patients currently treated with chemotherapy, and therefore you need to use the best chemotherapy that you have. it is less critical in the luminal and HER2-positive type. So we would like oncologists to take this message in the triple negative population and use nab instead of paclitaxel, and monitor the periphery sensory neuropathy carefully. 

Probably the most interesting combination so far are the checkpoint inhibitors, which there are trials investigating. There are also data combining Abraxane with carboplatin in the firstline setting and the metastatic setting, though there's a trial looking specifically into this combination. These are the two main combinations currently being investigated in triple negative breast cancer.

We have, since 2003, a registry ongoing collecting patients diagnosed with breast cancer during pregnancy. In parallel, we are also collecting data from patients who are very young with breast cancer, meaning diagnosed below the age of 40, as a control cohort. We collected tissue as well from our pregnant breast cancer patients, and we investigated if there is a different mutation pattern in the pregnant breast cancer patients compared to data which we retrieved from already collected data set.

What kind of clinical implications can this data have?

In essence, we found the main driver is probably the different cohorts. The pregnant breast cancer cohort was younger, and there were less HR-positive patients in this cohort compared to the TCHA dataset after matching the numbers, although this is the largest pregnant breast cancer cohort investigating somatic mutations in breast cancer. We also found that we have higher amounts of TP53 mutations in the pregnant and less PI3 kinase mutations, which could possibly explain the slight imbalances in the baseline characteristics.

We cannot derive any clinical conclusions from that. There was the rumor that patients diagnosed with breast cancer during pregnancy have worse outcomes due to the underlying biology. So far in the large dataset from our cohort of almost 500 patients and 800 controls, we could not demonstrate that the pregnant patients had a worse outcome. The worse outcome some other investigations have shown is mainly driven by the non-standard treatment of those patients. We wanted to see if we can see some biological differences by investigating the mutations in this cohort.

Sibylle Loibl, M.D., Ph.D., discusses the GeparSepto trial and what it means for women with breast cancer. 

Comparing Treatments in Breast Cancer Subsets

In order to advance the field of liver cancer treatment, it is crucial to understand personalized medicine and navigate the controversies around neoadjuvant treatment, says Michael Choti, M.D.

, Choti, professor and chair of surgery, UT Southwestern Medical Center, discusses the importance of biomarkers when it comes to choosing treatments, which treatments to choose for certain patients with GI cancer, and the improvement of systemic therapy.

Can you share some key points on liver-directed therapy?

This is a focus that is part of the School of GI Oncology to really emphasize the fact that cancer of liver, often metastatic to the liver, is a common pattern. Often it's an area that is probably associated with a complex management that involves medical oncologists, radiation oncologists, imaging, gastroenterology and even interventional radiology. The reason we have this as a particular focus of this course is that management of patients with liver metastases is often complex and often very multidisciplinary.

Are there any advances in managing liver cancer on the horizon?

There are significant advances that are happening. First, globally, just understanding personalized medicine and understanding better biomarkers to identify which patients may be better candidates for therapy directed to whatever specific organ, like the liver.

If we can understand, for example, prognostic biomarkers that can define which patients can derive benefit for surgical therapy from liver metastases, then that would be very advantageous. We're clearly making advances in that area. Similarly, we may identify better with predictive biomarkers for which patients may do better or worse with liver-directed therapies.

What is the potential for PD-1 inhibitors in liver cancer?

PD-1 inhibitors are a class of immunotherapy. I think that certainly that new class of agents offers a new ability &shy; — the ability to treat patients who in the past have not been candidates for systemic therapy.

What do you think we can expect within the next few years, as far as advances in treating liver cancer?

Significant changes are happening in how we treat patients with liver cancer. As a surgical oncologist, we're certainly increasing therapies, techniques, minimally invasive surgery, for example, and other approaches to treat patients more safely, and more aggressively in some cases, for liver cancer and liver metastatic disease. We're also having advances in the area of imaging, in the areas of other liver-directed therapies in terms of arterial approaches, ablation, and other ways.

Of course, systemic therapies are improving, and not only offer better, long-term outcomes for patients, but they may actually increase the opportunity with responses, for example, to immunotherapy or systemic therapies. We may actually be asked to have an increasingly aggressive approach of residual disease in the liver, for example.

In GI cancers in general, how do you decide which patient can receive one therapy and not the other?

The biology of GI cancers can vary, not just by the site of origin, but based on molecular genetics and other patterns based on how patients will do. How we decide on which patients receive which therapy is often multifactorial. It's based on team decisions, multidisciplinary tumor boards, and looking at the biology of the pattern. Not only the choice of which chemotherapy a patient may be offered, but also whether to be offered local therapy or surgical therapy for metastatic disease. Certainly in patients with localized GI cancer, surgical therapy is still the mainstay of curative therapy for patients with gastrointestinal malignancies.

Even with the advances of new agents and new therapies, these are still largely used in patients with incurable forms of cancer. So the ability to offer surgical therapy in patients with localized disease is still there, first and foremost, but there may be increasingly opportunities to offer local or surgical therapies, even in patients with more advanced disease as we're getting better with new systemic therapies.

What is the role of neoadjuvant treatment in liver cancer?

This has been, in the past, very controversial, as to whether to give treatment prior to surgical removal of a patient with cancer of the pancreas. Now that we have more effective systemic chemotherapy in patients with advanced pancreatic cancer, these are being introduced into patients who are operable. There's a clear enthusiasm in recommending pre-operative therapy in patients with operable pancreatic cancer. Clearly, as we're getting better with systemic chemotherapy, it may or may not be a pattern in whether or not we will integrate radiation, if at all, in patients with operable pancreatic cancer.

Michael Choti talks about what kind of advances can be expected in treating liver cancer, including PD-1 inhibitors and neoadjuvant treatment.

Greg Kennelty

Individualized Treatment Is Needed for mCRC Subset

Discussing the World Health Organization's New Brain Tumor Classification

Comparing Treatments in Breast Cancer Subsets

Expert Discusses What Advances to Expect in Liver Cancer

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