Shannon Connelly

case-based peer perspectives live dinner event, Massimo Cristofanilli, MD, discussed with a group of physicians the considerations he makes when deciding on treatment options for patients with breast cancer. Cristofanilli, a professor of medicine in the Hematology and Oncology Division at the Robert H. Lurie Comprehensive Cancer Center, Northwestern Feinberg School of Medicine, explained the options for treatment based on the case scenario of a woman with estrogen receptor (ER)positive breast cancer.

A 63-year-old woman with right-sided ductal carcinoma in situ (DCIS) refused endocrine therapy from her physician. She presented with a left-sided mass 13 months later.

Her liver function tests (LFTs) were mildly elevated and a CT scan showed 2 liver nodules, with the largest at 2 cm. A biopsy revealed grade 2 invasive ductal carcinoma, ER-positive, progesterone receptor (PR)-positive, HER2-negative, which was stage T3N1M1. She had an ECOG performance status of 0.

What are your initial impressions of this patient and case?

This is an ER-positive cancer; this is a patient with liver metastasis. This is a postmenopausal woman who had a diagnosis of right-sided DCIS that was treated with surgery and radiation and then she refused endocrine therapy for prevention, which is very important. Then 13 months later, she presents with a left-sided mass, now a palpable mass. She had some tests to see what was going on in the breast: mammogram, ultrasound, biopsy, and a blood test. The LFT showed mildly elevated levels. Because of that, we order a CT scan and try to identify if there are any other problems, and she does have 2 liver lesions. The largest is 2 cm.

The biopsy demonstrates that she has ER-positive disease. This is an ER-positive, metastatic diagnosis with de novo metastasis, bi-lateral breast cancer with an optimal performance status. The LFT may or may not be associated with her disease because the lesions are relatively small, and importantly, she has not been exposed to endocrine therapy. This opens up a number of possibilities.

We think about therapy right away. We want to rush to do something for this woman. Clearly, [there has been] relatively fast progression; it is an aggressive disease.

What are the therapeutic options for this patient?

There are a variety of intensive treatment options: endocrine therapy, CDK4/6 inhibitors, aromatase inhibitors [AIs], chemotherapy.

We start to think about a CDK4/6 inhibitor with an AI as a first-line option for de novo stage IV disease. Chemotherapy might not be a good recommendation [for this patient].

With regard to endocrine therapy and CDK4/6 inhibition, we talk about a number of clinical factors first: clinical presentation, age, menopausal strategy, etc. If this were a premenopausal woman, maybe you would have considered chemotherapy. If the tumor was larger it would not have made a difference, [because] she is at stage IV. [Looking at] ER and PR status, she has ER positivity. Pace of progression: She is not progressing, she has de novo disease. Extent of disease: major liver involvement. And, of course, the symptoms: She is symptomatic. She deserves a CDK4/6 inhibitor.

If she had received, let us say, Arimidex [anastrozole] for prevention, then [the use of an AI] would be a little bit different, not because of resistance but the possibility of resistance.

For this patient, we would use an AI and a CDK4/6 as first-line treatment. The National Comprehensive Cancer Network guidelines are very open in terms of the choices left to the physician,

meaning that you can pick and choose from this menu. When you look at the CDK4/6 inhibitors, you see that there are 3: abemaciclib [Verzenio], palbociclib [Ibrance], and ribociclib [Kisqali] with [an] AI, [and] with fulvestrant [Faslodex] for patients who progress on an AI. We keep building this list. In the past, we had everolimus [Afinitor] with exemestane, and there is a list of other agents that can be used later.

How do you decide which CDK4/6 inhibitor to use?

We have 3 clinical trials that have shown that when you use an AIin some cases it does not matter which AI&mdash;in combination with a CDK4/6, you definitely have an improvement in outcome. The [primary endpoint in all 3 trials] was median progression-free survival [PFS]. That was the first endpoint that brought the approval of these agents. The different ratios [between the 3] are pretty similar.

It is very difficult to compare the different studies in a way that is consistent, and we should never do that. But one thing that you need to remember is if you look at the median PFS, the control group is pretty consistent overall. Patients in PALOMA-2 were na&iuml;ve enough to prior metastatic treatment for endocrine therapythis allowed some endocrine therapy&mdash;but overall, there is a significant impact on PFS, [a] clinical benefit to the agent in overall response.

Describe the 3 CDK4/6 inhibitors that are approved for use in this setting and what clinicians should know about each.

Up front, the 3 agents appear to be similar in some respects, but when you start to go into the details of these agents, you see there are differences in the schedule, administration, dose, the adverse events [AEs], and the chemistry and targets. This relates to the fact that they are targeting CDK with different potency.

Palbociclib was the first-in-class. The starting dose was 125 mg daily at 3 weeks on, 1 week off; AEs include neutropenia [and thrombocytopenia], and there is a scale of adjustment to dose when it is necessary. Usually, everything happens in the beginning for this agent.

Ribociclib is a 200-mg tablet, [with a starting dose of] 600 mg daily, also at 3 weeks on, 1 off; [AEs seen with the agent include] neutropenia but also QTc [QT interval correct for heart rate] prolongation.

Abemaciclib usually starts at 200 mg continuously, can also be used at 150 mg daily. [AEs include] fatigue, but primarily diarrhea and neutropenia. We know how to manage these AEs.

How do the results of these trials affect how you treat patients with visceral disease?

Going back to the comparison of the different studies, the populations are relatively similar, the benefit is consistent across the different subtypes, and the PFS benefit is similar respective of age, and this is a population that is postmenopausal primarily.

When you look at [patients with] visceral metastases or no visceral metastases in the MONALEESA-2 trial, describing the lung and liver metastases, there is a pretty consistent [benefit with ribociclib].

These patients, in spite of being in the first line [and] in spite of being 30% or so de novo,

had visceral bone metastases, and the benefit is there. The patients with visceral disease, in general, had less benefit than nonvisceral and bone-only disease&hellip;Overall, the liver is a little more difficult to treat irrespective of whatever agent you use, including chemotherapy, of course. Some patients had received prior therapy, like AIs, only if they had [a disease-free interval] >12 months. Pretty much all the patients in the first line were not symptomatic and ER-positive overall.

Let us start looking at palbociclib in relation to the MONALEESA-2 trial in regard to the visceral sites. This starts to make sense at some point. In general, the benefit is the same in terms of visceral and nonvisceral disease. And if you look at the liver versus lung involvement [compared with] the control group, you start to realize that liver metastases have the most typical [resistance to therapy]: 8.4-month median PFS for single-agent letrozole compared to 13.6 months with lung involvement. The most consistent kind of resistant disease is the one in the liver. Also, you see the difference with the combination [13.7 months vs 22.2 months, respectively]. These patients do much worse as a group.

I was involved with the PALOMA-3 trialthe design and the presentation of the data. We presented [these] data because this study was more mature. PALOMA-3 was essential in the initial indication for palbociclib. We had enough follow-up to start looking at overall survival [OS]. Everybody is criticized one way or another for PFS [as an endpoint], because [they ask] &ldquo;What does it mean at the end of the day?&rdquo;

Having the survival data was very important because we started to see that there was a 6-month difference in OS, [but] there was no statistical significance [HR, 0.81;

= .09]. But when you look at the 2 different groups of patients with endocrine-therapy sensitivity and resistance, you can see that you can have up to a 10-month advantage in survival when you have an endocrine-sensitive clinically defined group. So clearly there is a group of patients for which&hellip;a CDK 4/6 inhibitor is not only associated with improved PFS but can also extend survival, and this is important.

MONARCH 3 is the trial that allows choices in terms of AIs. There is consistent benefit even in patients who had prior AI or prior endocrine therapy. The one important part when we got to the MONARCH 2 and the MONARCH 3 trials is that when we look at the difference within the placebo group, abemaciclib got a response in the different subsets of patients. For example, in the liver metastases group, there is a difference of 33% in the overall response rate [compared with placebo in MONARCH 2] and 37% in MONARCH 3.

This is very important, because now you start to use clinical trial data. Just seeing these manual different options, I know that they are similar, but they are not exactly the same. And how do I choose 1 of the 3 for a specific patient?

Do the AEs associated with abemaciclib worry you?

Everybody knows abemaciclib causes diarrhea. [Clinicians should make sure to use] diet counseling and patient education, because the last thing you want to do is dose modification. Obviously, if there is a great need to, then absolutely do it.

It is pretty much all individual; everybody has a different reaction. Some patients have difficulty, but we have also seen neutropenia with palbociclib, and that is difficult to manage, as well.

This patient was started on abemaciclib and letrozole. We wanted to start with a combination, and we thought that this was appropriate for this patient who was not symptomatic and had a little bit of liver abnormality, but nothing to be described as a crisis. There was no chemotherapy, just the CDK 4/6 inhibitor.

What would you use after failure on a CDK4/6 inhibitor?

I think the question as to what to do after [a] first line CDK4/6 inhibitor is, right now, a research question. The only thing that we can say is that the only data that were presented were in regard to the SOLAR-1 trial, suggesting that a PI3K inhibitor [alpelisib] could potentially be one of the choices.

It is not available right now, but approval may be coming. It still remains a research question, but it is not a reason to delay the use of a CDK4/6 inhibitor.

What if progressions occurred after the completion of endocrine therapy?

Let us say that disease progression occurred while she was on preventative therapy. While on adjuvant therapy, she had primary disease, so she was on some course of endocrine therapy. That would have been changing a little bit because that would have become resistant. Of course, we look at MONARCH 3, and there was a group of patients [who] had sensitive disease. They progressed within 36 months or so. You definitely use the time to progression or progression from endocrine therapy, adjuvant therapy, as a way to decide what to do.

Which single-agent AI would you use for this patient?

We know that there was a big use push to minimize the use of CDK4/6 inhibitors in the first line and to promote more first-line single agents. [The FALCON] study was presented a couple of times and published in

; it suggests that fulvestrant is better than anastrazole.

I do not think we disagree on that. This study was very interesting because a majority of these patients were never exposed to endocrine therapy in the adjuvant setting and the majority were newly diagnosed, so it was a unique population.

In patients [who] have bone-only disease, they will have more benefit from fulvestrant and less from [anastrozole]. But with visceral metastases, there is no question that there is no difference. When you look at the numbers, it is difficult to compare; it is much less in terms of PFS when compared to the combination.

What are the major take-away points from these data?

Bottom line, clearly any patient with de novo disease with visceral metastases or bone disease in the first line deserves a CDK4/6 inhibitor. If they are endocrine-therapy sensitive, the benefit may translate eventually into a long-term OS benefit. If they are endocrine-therapy resistant, we do not know, and time will tell. But we need to start thinking about what to do after [CDK4/6 inhibitors], and of course, PI3K inhibitors may be an option. The 3 agents are similar according to the published data in the first- and second-line settings, but they are different drugs. For some indications, one may be better than others. For example, with liver metastases, abemaciclib could be a better choice. The drug is well tolerated overall. We know how to manage some of the AEs without any problems.

We are having a lot of success with these patients. I think a lot of people can tell that the ER-positive group has a lot of options. I have a patient [who] has been on a CDK4/6 inhibitor for 4 years, and they have no AEs. These are really changing and improving the patient&rsquo;s quality of life.

Is the continuous dosing of abemaciclib an advantage over similar agents?

It could be. It is hard to tell, because there is no direct comparison. Nobody is going to do a direct comparison. I know that ribociclib is going to eventually be [administered as a] continuous dose, because reducing the dose may also take care of the QTc elongation. When you use this agent, in particular when you know the AE profile, the idea is to treat as long as possible continuously. The only reason why the ribociclib and the palbociclib initially require the one-week-off schedule is because of the neutropenia. You know that recovery is very important. The is no direct correlation between the dose and the efficacy. Certainly, with abemaciclib, the advantage is that it is the only one with a single-agent activity.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Breast Cancer. Version 1.2019. NCCN website. nccn.org/professionals/physician_gls/pdf/breast.pdf. Published March 14, 2019. Accessed March 25, 2019.

Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer.

2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.

Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer.

2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709.

Articles

During a recent Targeted Oncology case-based peer perspectives live dinner event, Massimo Cristofanilli, MD, explained the options for treatment based on the case scenario of a woman with ER-positive breast cancer. 
&nbsp;

Cristofanilli Reviews CDK 4/6 Inhibitors in the Case of a Patient With ER-Positive Breast Cancer

live case-based peer perspectives presentation, Tanios Bekaii-Saab, MD, discussed with a group of physicians the treatment options for patients with gastrointestinal cancers and the characteristics that influence his decision making. Bekaii-Saab, a professor of medicine, Mayo Clinic College of Medicine and Science, and the leader of the Gastrointestinal Cancer Program at Mayo Clinic Cancer Center, explained his clinical decisions based on the case scenario of one patient with colorectal cancer (CRC) and one with hepatocellular carcinoma (HCC).

A 53-year-old Caucasian man without a previous colonoscopy presented to his primary care physician, complaining of rectal bleeding and abdominal tenderness. He had a medical history of hypertension, which was well controlled on a beta-blocker. His mother had died from complications of breast cancer.

He underwent a colonoscopy with biopsy which revealed an ulcerated nonobstructive mass was noted in the descending colon. Pathology results confirmed poorly differentiated adenocarcinoma. Limited molecular testing suggested

status was not available and he also had microsatellite-stable disease. A CT of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was diagnosed with metastatic adenocarcinoma of the right colon; T4N0M1.

The patient was started on FOLFOXIRI (irinotecan, fluorouracil, folinic acid, and oxaliplatin) and bevacizumab (Avastin); therapy was well tolerated after management of grade 2 neutropenia.

Two months later, a follow-up scan showed a 35% decrease in his liver lesions and the lung lesion. He continued on FOLFOXIRI plus bevacizumab for 4 months and then developed grade 1 neuropathy. Eventually, he was switched to FOLFIRI (irinotecan, fluorouracil, and folinic acid) plus bevacizumab.

He did well until 4 months later, when he developed more fatigue and started losing weight. Imaging showed a new 2-cm lung lesion on the left side with pleural expansion and associated pleural effusion. He had an ECOG performance status of 1.

: What are your initial impressions of this patient?

This patient had limited genomic analysis. Most patients coming to your clinic probably do not have the basic information such as

The suggestion initially was that you still get some benefit from the EGFR inhibitors, but when you look at the cumulative data, they suggest that

mutations probably should exclude patients from receiving EGFR inhibitors.

So, what treatment should the patient get, based on the presence of a

At this point in time, it doesn&rsquo;t seem to matter for first-line therapy. Where it seems to matterand you will see more of this coming out this year&mdash;is [with] specific targeted therapies that will likely be approved for the

mutation, the patient started on FOLFOXIRI and bevacizumab. For those patients with

-mutated colorectal cancers [CRCs], it appears that the triplet therapy, when indicated, has a much better outcome than [it does for] patients receiving just a doublet like FOLFIRI [irinotecan, fluorouracil, and folinic acid] or FOLFOX [oxaliplatin, fluorouracil, and folinic acid], plus or minus bevacizumab. Bevacizumab enters into the equation just because this was how the study was performed. We don&rsquo;t know if that adds value or not, but overall, those patients, if eligible, have the

V600E [mutation]. If you look at the data with the doublets, it becomes very apparent that those patients have very poor response rates. In fact, most of these patients have an average survival of 9 to 11 months with doublet therapy. As we said, they don&rsquo;t respond to EGFR inhibitors, so triplet therapy with bevacizumab seems to be a better standard.

This patient received FOLFOXIRI and bevacizumab, then had scans showing a 55% decrease in the liver lesions and the lung lesions, so the patient was doing wellnot a lot of toxicities. As you know, these triplet therapies are hit and miss in terms of toxicities. Some [patients] end up with horrendous toxicities, and some, surprisingly, end up with almost no toxicities.

The patient continued with FOLFOXIRI/bevacizumab for 4 months and then got grade 1 neuropathy. The oxaliplatin neuropathy stepped in again at that point, so you decided to drop the oxaliplatin and just continue with FOLFIRI and bevacizumab. This patient did well for another 4 months and then started getting more fatigue, losing more weight, and then&hellip;had a lung lesion but also started developing pleural effusions. There&rsquo;s definitely progression, and the ECOG performance status is now 1. This is a patient that had FOLFOXIRI plus bevacizumab, went to FOLFIRI/bevacizumab, went for 8 months, which most of these patients have a tough time even getting to, with a decent response, and now is progressing again.

What would be the treatment options at this point?

In the National Comprehensive Cancer Network [NCCN] guidelines,

there is actually a study from SWOG that led to an indication, which included vemurafenib [Zelboraf] plus cetuximab plus irinotecan as an option; a BRAF inhibitor, an anti-EGFR antibody, plus chemotherapy.

That you can get reimbursed for, because it&rsquo;s on the NCCN guidelines. This study essentially randomized patients to vemurafenib/rituximab/irinotecan versus irinotecan and cetuximab. It showed a slight OS advantage, which led to that indication going on the guideline.

The phase III BEACON study reported the [safety lead-in phase] of the trial, which is now published in the

And that includes a BRAF inhibitor, a MEK inhibitor, and an anti-EGFR antibody, cetuximab. So, it&rsquo;s encorafenib [Braftovi], binimetinib [Mektovi], and cetuximab. The thought is, unlike with melanoma where you target tumor with a BRAF inhibitor and you can get a response, albeit a short-lived response, in CRC, the response rate with single-agent BRAF inhibition is close to 5% or less and the progression-free survival [PFS] is about 2 months. It seems that as you block BRAF and you block MEK even underneath, EGFR essentially becomes a primary drug for colon cancer, and that&rsquo;s why it makes sense at that point in time to introduce the EGFR inhibitors.

Interim study results from the BEACON trial were published in a press release. In data from 665 patients, the median overall survival [OS] was 9.0 months versus 5.4 months, [HR 0.52, 95% CI, (0.39-0.70);

<.0001]; and out of 331 patients, the objective response rate was 26.1% versus 1.9% [

<.0001] for the triplet and the control arms, respectively.

That is likely going to become our standard, probably in the next year or so, after they go through all the commotion. The press release that published these data declared the results to be positive.

[The SWOG 1406 trial] is now part of the NCCN guidelines, so today this is probably what you have to refer to, because that is what [oncologists can] get reimbursed for, and that&rsquo;s vemurafenib/cetuximab/irinotecan. This was a phase II randomized study of about 100 patients. The hazard ratio is about 0.48. Some groups of patients do extremely badly, regardless of how you treat them, but this is the group that seems to do the best.

The BEACON study randomized patients to triplet encorafenib/binimetinib/cetuximab, and the control was FOLFIRI/cetuximab. The problem with the study is that it accrued very poorly in the United States, because most patients would have had access to a BRAF inhibitor from the NCCN guideline indication. This study completed, actually, and the results will be presented soon and will make their way to the FDA. [In data from] the first 30 patients, the median overall survival [OS] was not yet reachedit&rsquo;s probably going to be about 16-plus months&mdash;and the response rate was 48%.

mutation is in about 6% to 7% of all patients with left-sided tumors. If you take all patients with colon cancer [and] look at the literature, it suggests it&rsquo;s anywhere between 6% and 10%. The reality is, if you take all patients with CRC, it&rsquo;s about 3% to 4%, but for the left-sided tumors, it&rsquo;s about 6%.

These are not common, but they&rsquo;re not uncommon. If you see enough patients with CRC, you&rsquo;re going to see a bunch of

[mutations]. These patients do incredibly badly. With this doublet and this triplet that I think is coming through BEACON, you&rsquo;re going to change for at least half of the patients the natural history of the cancer. Some of these patients actually are surviving for more than a year or 2.

Typically, for a target to be relevant, you can&rsquo;t have 2 alterations in the same pathway, otherwise it would be a random alteration that the cancer itself doesn&rsquo;t depend on. Those alterations and 1 element of the pathway that is likely to be a driver, like

In this case, because of the fact that right now you can only have access to vemurafenib, you can certainly change cetuximab for panitumumab [Vectibix] and get about the same [results] with irinotecan. The patient ended up with a good response, then progressed, and now has multiple new lesions. Performance status remains at 1.

What do you do with this patient after progression on second-line treatment?

Let&rsquo;s say you don&rsquo;t have a clinical trial. Regorafenib [Stivarga] and TAS-102 [Lonsurf] are both reasonable options. Good performance status, good liver function; everything else seems to be reasonable.

We&rsquo;re actually about to publish the [ReDOS] study in

. We presented this at ASCO [American Society of Clinical Oncology Annual Meeting] and the [Gastrointestinal Cancers Symposium]. This was a phase II randomized study that looked at starting [regorafenib] at 80 mg, then going to 120 mg, with a goal of getting to 160 mg in the absence of toxicities. Arm B was given 160 mg, the standard. The primary endpoint of the study was the proportion of patients able to initiate cycle 3. This was 120 patients; the primary endpoint focused on whether the patients were able to start cycle 3. In other words, they hadn&rsquo;t progressed on a scan, so that&rsquo;s a measure of efficacy. They were able to get to cycle 3 because they didn&rsquo;t have any toxicities that started from doing this. We were hoping for 50% improvement with the dose-escalation strategy versus without it. In fact, the study met its primary endpoint, so this was a positive trial. About 43% of the patients went from 80 mg to 120 mg to 160 mg, able to make it to cycle 3, versus just 25% in arm B.

What was interesting was the OS of the patients9 months with the regorafenib dose-escalation arm versus 5.9 months with regorafenib at 160 mg. In other words, when you look at the CORRECT trial, the initial trial that looked at regorafenib 160 mg, the primary endpoint was survival, and it was about 6 months.

The standard arm on the ReDOS trial was also 6 months with 160 mg, but when you look at the 80 mg to 120 mg to 160 mg, the dose-escalation strategy, the last updated data were close to 10 months, which was superior to 160 mg. But it didn&rsquo;t reach statistical significancemind you, this was a secondary endpoint. Progression-free survival is now close to 3 months versus 2 months with 160 mg. Again, this was not statistically significant.

The interesting part of the study is that as you go over the dose-escalation strategy, the patients not only end up with an improved outcome but also seem to have fewer toxicities, less hand-foot syndrome, less hypertension, and significantly less fatigue, but they also have the quality of life preserved. What we have seen is that patients do not lose any of their quality of life when you measure it across the spectrum, whereby with 160 mg, the patients&rsquo; quality of life dips around week 2, which is where we expect the toxicities to start going up. Regorafenib&rsquo;s toxicities show up early, and actually, the severity is the worst in the first 4 weeks, so it&rsquo;s quick and bad when it happens. For the dose-escalation strategy, that toxicity did not seem to be significant for those patients, and the quality of life ended up being pretty well preserved all the way through. For those patients who just went straight on the 160-mg dose, their quality of life dipped at week 2 and then recovered by week 4, but they never recovered completely after week 4. This now is part of the NCCN guidelines, and it&rsquo;s likely to change some of the label of this to add the option of dose escalation.

What are your impressions of the patient at the point of third-line therapy and beyond?

The patient went on regorafenib with 80 mg, 120 mg, and then 160 mg and then received TAS-102, and then the patient progressed. The patient still has a good performance status and wishes to be treated. But frankly, you&rsquo;ve consumed almost all your treatment options.

fusion. How would the patient be treated then?

fusions have a presence in about 0.5% to 0.7% of colon cancers, so this is a lucky patient if you find the

fusion. This comes from the study [of larotrectinib (Vitrakvi)], which was a tumor-agnostic study&hellip;[NTRK] is a target across all diseases, so the study included any patient with a TRK-fusion cancer and essentially showed these results, [which] are actually short of amazing for many patients. You do see some effects that are very similar to what you observe with microsatellite instability [MSI]high patients and immune therapy. In this particular study, 7% of the patients had colon cancer. You can see some of these patients had a complete response [CR], as well as a partial response [PR]. You can see the majority had a response, many had CRs, many had PRs, and some of these responses actually happened later rather than earlier, so they continued to progress into a better response.

fusions [via DNA sequencing]; Caris Foundation and Tempus [tests detect&nbsp;

fusions via both DNA and RNA sequencing]. The problem with this is that for fusions you need to capture both DNA and RNA, &nbsp;to be able to get close to 100%. &nbsp;Even the tests that are broadly available commercially will still lose some of the&nbsp;

fusions, especially in the absence of RNA seq. That&rsquo;s 1 of the problems, but most companies are working on improving the tests.

fusion, you want this drug [larotrectinib]. These are refractory patients; they progressed on multiple lines of therapy.

Another study was with entrectinib. You can see very similar results in colon cancer7% of patients. In sarcoma and lung cancer, 19% and 24%. This is a piece of the pie of the patients who were recruited. When you look at the percentage of patients with colon cancer who have

fusions, that&rsquo;s about 0.5% to 0.7%, so you have to screen at least 100 patients to maybe find 1. With MSI high, you have to screen 100 to find 4 in colon cancer. These are rare, but if you&rsquo;re that 1 patient, that makes a huge difference.

amplification instead? How would he have been treated?

In colon cancer, HER2 amplifications can be found in about 4% to 5% of patients. HER2 amplifications are important for a lot of reasons. A number of studies are looking at HER2. HER2 has 2 things that are important; that&rsquo;s why I think every patient with colon cancer, in addition to

, should also have [testing done for] HER2 amplification, so at minimum, these are the 5 things you need to have tested for in your patients with CRC.

[One] reason HER2 is important is that clinical trials look at HER2-targeted therapies in colon cancer, but the other thing that is very important is that HER2 amplifications actually confer resistance to EGFR inhibitors. So a patient could be

wild-type but have a HER2-amplified tumor; these patients do not respond to EGFR inhibitors. In fact, 2 studies1 from MD Anderson and 1 from the Italian group, Siena et al&mdash;showed similarly that if you have HER2-amplified CRC, you have 0% likelihood of responding to an EGFR inhibitor. Now, if you track back, it makes sense. Biologically, one of the mechanisms in which you get resistance to EGFR is by essentially amplifying all the other family members, HER2 and HER3. [They] are primary drivers of resistance for HER1 or EGFR. It makes biological sense. For that, it is very important to think of HER2 amplification because it can affect how you treat those patients. It&rsquo;s primarily on the left side, where you have most of the&nbsp;

One study is looking at tucatinib and trastuzumab [Herceptin] in amplified colon cancer [NCT03043313]. We have about 25 patients on this study; it&rsquo;s going to be expanded to about 100. In about 4% of patients, max, you will have HER2 amplification. A study from Italy that was published in

looked at lapatinib [Tykerb] and trastuzumab. It showed some impressive responses in some patients that were durable.

The study from Genentech that included trastuzumab and pertuzumab [Perjeta] actually wasn&rsquo;t that impressive, so it doesn&rsquo;t look like putting 2 antibodies together is going to make much of an impact. It seems that a tyrosine kinase inhibitor [TKI] and trastuzumab have a much better effect. Tucatinib is an oral agentit&rsquo;s a TKI; it&rsquo;s much cleaner than lapatinib in targeting HER2. I can tell you that we&rsquo;re starting to see some interesting responses with the combination. That&rsquo;s something to keep in mind for patients with colon cancer that may have a HER2 amplification.

A 63-year-old Asian man with chronic hepatitis B virus (HBV) infection was referred for further imaging studies after routine ultrasound surveillance for hepatocellular carcinoma (HCC) revealed suspicious findings.

-fetoprotein (AFP) level was 5400 IU/mL. He had a Child-Pugh score of A due to: platelets of 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin, 3.5 g/dL; no hepatic encephalopathy; and no present ascites.

A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm but no extrahepatic disease; no cirrhosis. Biopsy findings showed grade 2 HCC with moderate fibrosis. The patient underwent liver resection with an R0 margin.

During a recent&nbsp;Targeted Oncology&nbsp;live case-based peer perspectives presentation, Tanios Bekaii-Saab, MD, discussed with a group of physicians the treatment options for patients with gastrointestinal cancers and the characteristics that influence his decision making. Bekaii-Saab explained his clinical decisions based on the case scenario of one patient with colorectal cancer and one with hepatocellular carcinoma.

Bekaii-Saab Considers TKI Therapy to Treat Patients With Advanced GI Cancers

Patients with aggressive papillary thyroid cancer (PTC) may be good candidates for treatment with antiPD-(L)1 immunotherapy due to elevated levels of serum PD-L1, according to findings from a new study presented during the 2019 Combined Otolaryngology Spring Meetings held in Austin, TX.

In a poster presentation, investigators from Louisiana State University Health Sciences Center, led by Lindsay Boven, MD, set out to determine if patients with aggressive PTC were candidates for antiPD-(L)1 agents and if aggressive PTC is linked with the presence of

V600E mutations. The investigators additionally looked at the association between

PTC accounts for 80% of all thyroid cancers and is typically associated with a good prognosis. Aside from radioactive iodine, which is the standard of care, there are limited treatment options available for the 5% of patients who have aggressive PTC and can become refractory to radioactive iodine treatment.

Treatment with the antiPD-1 agents nivolumab (Opdivo) and pembrolizumab (Keytruda) has demonstrated therapeutic effects especially in patients with melanoma. Similarly to PTC, approximately half of all patients with melanoma have a

V600E mutation, which is typically associated with a poorer prognosis. Increased levels of PD-L1 are typically seen in patients with melanoma harboring

In the study, investigators determined the serum PD-L1 levels in 38 benign, 30 normal, 11 aggressive, and 14 non-aggressive PTC samples using the enzyme-linked immunosorbent assay (ELISA). Testing for the presence of

V600E mutations was performed on 14 non-aggressive and 10 aggressive PTC samples using immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tumor samples. PD-L1 levels were measured using polymerase chain reaction (PCR) in 13

V600Enegative PTC samples. Statistical significance was measured using analysis of variance (ANOVA).

Aggressive PTC in this study was defined as having one of the following features: extrathyroidal extension, an aggressive histology (tall cell, solid cell, columnar cell, and diffuse sclerosing variant), or distant metastases.

Significantly higher serum PD-L1 levels were seen in tumors with aggressive PTC compared with normal (

= .0001), and average levels in aggressive PTC samples were significantly higher than in non-aggressive thyroid cancers (

<.03). The average serum PD-L1 levels were not significantly different between non-aggressive PTC and normal (

In addition, among 10 aggressive PTC samples and 14 non-aggressive PTC samples tested for

V600E using both PCR and IHC methods, 54% of the cohort was

V600Epositive and 50% of aggressive PTC samples tested positive for

V600E mutations. There was no significant correlation seen by either method between serum PD-L1 levels and

&ldquo;These data suggest that patients with aggressive PTC have elevated serum PD-L1 levels and those with unresectable or refractory disease could potentially benefit from antiPD-L1 immunotherapy. Both aggressive PTC and PD-L1 levels did not appear to correlate with the presence of

mutation as a prognostic marker is controversial,&rdquo; the investigators wrote in their poster. They also suggested that intertumoral heterogeneity could contribute to

Boven L, Terhoeve S, Gundale A, et al. The Role of Anti-PD-L1 Immunotherapy in Aggressive Papillary Thyroid Carcinoma. Poster presented at: 2019 20AACR-AHNS Head and Neck Cancer Conference; Austin, TX; April 29-30, 2019. Abstract D018.

https://www.researchposters.com/display_posters.aspx?code=COSM2019?rel=0?rel=0

Patients with aggressive papillary thyroid cancer may be good candidates for treatment with anti&ndash;PD-(L)1 immunotherapy due to elevated levels of serum PD-L1, according to findings from a new study presented during the 2019 AACR-AHNS Head and Neck Cancer Conference.

Anti-PD-L1 Therapy May Have Benefit in Aggressive Papillary Thyroid Cancer

Genomic testing, such as next-generation sequencing (NGS), has become increasingly more prevalent in oncology and is essential to patient care, explained Olga K. Weinberg, MD.

One of the ongoing challenges with reading the results of NGS, however, is determining which mutations are clinically relevant and which currently have no clinical significance. The role of NGS will continue to shift as more information is uncovered about the significance of different mutations, Weinberg said.

&ldquo;What was [originally] felt to be not a real mutation, in the next few years as we learn more about that specific type of mutation, we may figure out that it was a real mutation and maybe it is clinically significant. As our landscape of understanding the results that we're getting back is changing, that also impacts our clinical practice,&rdquo; said Weinberg.

, Weinberg, director of hematopathology and flow cytometry, Department of Pathology, and assistant professor of pathology, Harvard Medical School, discussed how genomic testing has evolved over the years and how she envisions the role of NGS will change as more is learned about genetic mutations.

: Can you discuss the importance of genomic testing?

In a setting of hematopoietic neoplasms, genetic testing is very important. It plays a role both in diagnosis and prognosis. It's especially important in acute leukemia where it helps us pick out patients who would do well or who may not do well, and therefore, targets therapy.

: What type of testing is typically ordered?

When we say genetic testing, there are different kinds of genetic testing. For a very long time, people were doing karyotype testing, which is still the gold standard. [That is] where you take a tissue like a bone marrow or a peripheral blood and you grow the cells and see if they have a normal number of cells and a normal number of chromosomes, or if they have loss of chromosomes or if they have moved around. That's a karyotype [test].

You can also do molecular testing where you look for mutations. Some of those could be acquired mutations or things you've had your whole life, or things that are associated with a neoplasm. Genetic testing is varied, and we do different types depending on the disease that we're working with.

: With molecular testing, are there any complications with regard to determining the difference between a fusion and a mutation?

Yes, you would generally need a different test to pick up a fusion versus a mutation. A mutation is a change at the molecular level, like a nuclear level, versus with a fusion you're taking parts of chromosomes and they're coming together in a particular way.

: How can the results of genomic testing be used in prognosis and diagnosis?

There are some entities that are defined based on the abnormality that you see. For example, in a setting of acute myeloid leukemia, if you have translocations between chromosomes 15;17, that's defined as acute prolymphocytic leukemia. That has implications for therapies because there's a very specific therapy for that type of acute leukemia, but in other types of acute leukemias, if you have mutations like an

mutation, it helps to pick out patients that may respond well to induction or may need more intensive therapy like consolidation and transplant.

: Now that there are many biomarkers that can lead treatment toward immunotherapy, is NGS becoming more prevalent?

NGS is probably more common in the world of myeloid neoplasms versus a lot of immunotherapy treatments now are more popular in the lymphoid world. But, NGS is definitely becoming a much more frequently used test that is applicable in both lymphoid and myeloid malignancies.

: Are there challenges in terms of reading the results of a test?

Sometimes. Depending on where a test is obtained. For example, in an NGS test we may see mutations that are real versus mutations that are not significant, or they are what is called a &ldquo;variant of unknown significance.&rdquo; Different laboratories may not make a distinction between those 2 mutations, they may just list all the mutations they found and then it's up to the person reading that report to figure out whether those mutations are real or not.

You can imagine that can be very challenging for a clinician that is very busy or a pathologist that is busy and the results may just get reported versus other laboratories might make a distinction. There is also an added challenge in that we learn more about these mutations as time goes on and we use NGS both in research and in the clinical setting. What was [originally] felt to be not a real mutation, in a few years as we learn more about that specific type of mutation, we may figure out that it was a real mutation and maybe it is clinically significant. As our landscape of understanding the results that we're getting back is changing, that also impacts our clinical practice.

: How do you see the use of genetic testing evolving going forward?

Olga K. Weinberg, MD, discusses how genomic testing has evolved over the years and how she envisions the role of NGS will change as more is learned about genetic mutations.&nbsp;

Shannon Connelly | Authors

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