Lisa Miller

After publishing them in October 2016,the National Comprehensive Cancer Network (NCCN) is already seeking to update and expand their guidelines for diagnosing and treating patients with myeloproliferative neoplasms (MPNs).

The guidelines focused initially on diagnosing each of the MPNs and treatment options for patients with myelofibrosis, as that was the disease type with the greatest unmet need, Ruben A. Mesa, M.D., explained in an interview with 

 following his presentation at the 2017 NCCN Annual Conference.

“The myeloproliferative neoplasms were probably one of the most significant of the hematologic malignancies that did not yet have NCCN guidelines,” said Mesa, a professor of medicine and chair of hematology at Mayo Clinic in Phoenix, and chair of the panel for the NCCN guidelines on MPNs. “The guidelines are very helpful in terms of improving quality of care by providing more homogeneity of care in the US, trying to bring in current evidence regarding treatment that can be utilized, as well as clarifying the role of a variety of things, ranging from transplantation to therapies.”

The guidelines look to explain the criteria for diagnosing each of the MPNs, including the World Health Organization’s (WHO) recent update to the classification of MPNs, and risk assessment. Yet currently treatment options are only included for patients with myelofibrosis in this edition of the guidelines. Treatment guidelines for patients with polycythemia vera (PV) or essential thrombocythemia (ET) are expected in the update, which Mesa remarked are expected in the summer of this year.

The myelofibrosis guidelines incorporate scoring systems for risk stratification, including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS) and the DIPSS-Plus. Mesa also noted that the guidelines endorse the 2013 International Working Group for Myelofibrosis Research and Treatment and European LeukemiaNet consensus response criteria, as well as the scoring system for total symptom burden.

“In myelofibrosis there are clinical improvement criteria that can stand alone. You can have reduction in splenomegaly that counts as a response. What that leads to for the clinical decision making is more subtle, and like all of these guidelines, they are married to clinical experience and expertise in terms of the character of response, and how that balances against any negatives that come with the treatment in terms of side effects or toxicities, as well as expense,” he said.

The guidelines also describe the prognostic significance of a number of common mutations in patients with primary myelofibrosis. Patients with an MPL W515L/K mutation, for example, have a higher risk of thrombosis compared with patients who have a CALR mutation, and they usually have an intermediate prognosis. Those who do not have JAK2, MPL or CALR mutations have an interior prognosis compared to patients with these driver mutations, with lower leukemia-free and overall survival rates. Patients with TP53 mutations are associated with a greater risk for transformation to acute myeloid leukemia.

 For patients with low-risk asymptomatic myelofibrosis, the guidelines recommend either observation for signs and symptoms of disease progression or a clinical trial. For symptomatic patients who are low-risk, the guidelines suggest interferons, a clinical trial, or Jakafi (ruxolitinib)—the only FDA-approved targeted agent for patients with myelofibrosis. Jakafi, a JAK1/2 inhibitor, is also recommended for patients with intermediate-1 and -2 disease, especially for those with intermediate-2 disease who are not candidates for transplant and have a high platelet count.

“Ruxolitinib is the only FDA-approved therapy, so obviously, it leaves you somewhat challenged when you fail that therapy,” Mesa said. “That’s the greatest unmet need and certainly many of the current clinical trials are aimed at trying to assist patients that have ‘failed ruxolitinib.’”

Although the guidelines do consider some options for when a patient is Jakafi -intolerant or resistant, including agents such as fludarabine and busulfan, they strongly encourage clinical trials. However, Mesa noted that in the expected updates to the MPN guidelines, they will delve further into more options for patients following progression on Jakafi.

Mesa also addressed in his presentation several promising second-line agents currently in development, including pacritinib, momelotinib, imetelstat and PRM-151. “We’ve seen data recently that certainly was encouraging. Although neither agent is approved yet, both pacritinib and momelotinib had beneficial data in that second-line setting. Data from two clinical trials are eagerly anticipated for PRM-151, the anti-fibrosing agent, as well as imetelstat. Those are two second-lines studies that are of great interest,” Mesa said.

“We desperately need other agents approved because we really only have one approved drug: ruxolitinib…. If a second drug becomes approved we will undoubtedly work to revise the guidelines in a very rapid fashion to provide clarity and situational use,” Mesa continued.

He remarked that the guidelines are a starting point for oncologists who are less familiar with diagnosing and treating patients with these diseases, yet the experience of oncologists more familiar with MPNs could outweigh the recommendations in the guidelines.

“We’re hopeful that [the guidelines] will be a good resource for community oncologists in clarifying a range of issues with these diseases,” Mesa concluded. “How one walks that path, there’s a lot of individual factors and clinical experience that are highly relevant.”

Articles

NCCN May Already Be Updating MPN Guidelines

Immunotherapy efficacy may be compromised if the patient takes antibiotics up to a month before treatment, according to the results of a retrospective analysis presented during a presscast of the 2017 Genitourinary Cancers Symposium, which raised concern about the relationship between gut microbacteria and antibiotics and their effect on immune checkpoint blockade agents.

In patients with metastatic renal cell carcinoma (mRCC), patients who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate when treated with checkpoint inhibitor immunotherapy than those who had not received antibiotics of 2.3 versus 8.1 months, respectively.

Previous preclinical studies using mouse models have suggested an association between antibiotics and the efficacy of immune checkpoint blockade agents. 

“This is the first analysis evaluating the impact of antibiotics on outcome in mRCC patients treated in the era of immune checkpoint blockade,” said investigator Lisa Derosa, M.D., Ph.D. candidate, of the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Researchers analyzed 80 patients with mRCC who were being treated with checkpoint inhibitors on trials at the Gustave Roussy institute. Immunotherapy treatments included single-agent anti—PD-1/PD-L1 therapy (67 patients), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor (10 patients), and a combination of anti–PD-L1 therapy and Avastin (bevacizumab; three patients).

A majority of the enrolled patients were male (65 percent), 88 percent had a clear-cell histology, and 80 percent of the patients had prior nephrectomy. Twenty-one percent had favorable disease by International mRCC Database Consortium (IMDC) risk standards, 57 percent had intermediate IMDC risk, and 22 percent had poor-risk disease. Sixteen patients (20 percent) had received antibiotics up to one month prior to starting treatment with immunotherapy, including mostly beta-lactamases or fluoroquinolones.

At a median follow-up of six months, overall survival (OS) results were not yet able to be reached in the overall population, but a negative trend was already noted for patients who received prior antibiotics. The objective response rate also favored patients who had not received antibiotics.

In a subgroup of 62 patients who were treated with Opdivo (nivolumab) monotherapy, patients who had not taken antibiotics showed a greater PFS rate, which also achieved statistical significance. OS in the Opdivo monotherapy subgroup was also significantly higher in patients who had not taken recent antibiotics.

 “Derosa shows that antibiotic therapy may have a direct impact on how well the PD-1 inhibitor nivolumab works in patients with kidney cancer,” said Sumanta K. Pal, M.D., who moderated the presentation.

A multivariate analysis for prognostic risk factors showed a hazard ratio of 4.17 for patients who had not received antibiotics compared with those that had taken antibiotics. Patients with a lower Karnofsky performance statuses also showed an increased hazard ratio.

“Immune-based therapies for cancer may have a complex interplay with the host’s microbiome,” commented Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”

Derosa stated that the data was preliminary but that it encouraged longer follow-up and further studies to confirm the hypothesis of the study.

“The observations that Derosa makes have some consistency with preclinical observation,” Pal said. “We may be able to offer some insights as to whether or not bacterial composition of the gut could affect clinical outcomes and that might help us guide antibiotic usage.” Pal also suggested that these findings are not yet mature enough to impact clinical practice. The researchers plan to enroll additional patients in this study to investigate the mechanism of action. Other studies exploring the relationship between antibiotics and the efficacy of immunotherapy agents in lung cancer and kidney cancer are ongoing.

Patients with metastatic kidney cancer may see a decreased efficacy of their immunotherapy regimen if they recently took antibiotics.

Antibiotics May Compromise Immunotherapy Efficacy in Kidney Cancer

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) accounts for more than 20 percent of all adult patients with ALL and is correlated with poor outcomes, according to a study in the 

The study evaluated the prevalence and genomic landscape of Ph-like ALL in this patient population with the intention of driving future clinical trials toward common targetable rearrangements in this subgroup.

“It’s basic genomic research but it has enormous translational implications,” said Charles Mullighan, M.D., M.B.B.S., a corresponding author of the report, in an interview with 

. “If one can identify these patients, they are excellent candidates for the addition of tyrosine kinase inhibitor (TKI) therapy.”

Researchers examined samples from 798 patients with B-cell ALL between the ages of 21 and 86. Gene-expression profiling was performed on the samples and patients were classified according to a coefficient (0-1) based on analysis of a 15-gene quantitative reverse transcriptase polymerase chain reaction low-density array. Patients with a coefficient of 0.5 to 1 were classified as having Ph-like ALL. In the study, 194 patients (24.3 percent) were found to have Ph-like ALL.

BCR-ABL1—rearranged ALL was identified in 23.2 percent of the patients and MLL-rearranged ALL was identifed in 15.4 percent.

The patient population was divided into three groups based on age: young adult patients (aged 21-39; 344 patients), adult patients (aged 40-59; 304 patients), and older adult patients (aged 60-861; 150 patients). The prevalence of Ph-like ALL was greatest among young adult patients at 27.9 percent. Adult patients had a frequency of Ph-like ALL of 20.4 percent and older adult patients, 24 percent.

Patients with non—Ph-like ALL had better survival rates than patients with Ph-like ALL with a five-year event-free survival (EFS) rate of 49.3 percent versus 22.5. The five-year overall survival (OS) rate for patients with non– Ph-like ALL was 52.4 percent versus 28.8 percent.

Survival disparities between patients with Ph-like ALL and non—Ph-like ALL were increased in younger patients. The five-year EFS rate for young adult patients with Ph-like ALL was 24.1 percent versus 60.5 percent. For adult patients with Ph-like ALL the five-year EFS was 21.4 percent versus 38.7 percent for non– Ph-like ALL. Five-year OS for young adults with Ph-like ALL was 25.4 percent versus 64.2 percent. OS for adult patients with Ph-like ALL was 27 percent versus 44.9 percent.

The survival differences for older adult patients with Ph-like ALL were lower than older adults with non—Ph-like ALL, but these differences were not statistically significant. Older adult patients with Ph-like ALL had a three-year EFS of 8 percent and a three-year OS of 13.5 percent versus 33.3 percent and 37.9 percent, respectively, for older adult patients with non–Ph-like ALL. The authors noted that the smaller group of older adult patients could have affected the significance of these findings.

Ph-positive ALL has been studied in depth in pediatric and adult patients, as this well-known subtype was associated with a poor outcome. However, the rate of Ph-like ALL—which Mullighan notes has a similar gene expression profile to Ph-positive ALL but lacks BCR-ABL1&mdash;in older patients was previously unknown.

“It had been known for many years that the frequency of Ph-positive leukemia, BCR-ABL—positive ALL, rises with increasing age. There are some data suggesting that the frequency of Ph-like ALL may not continually increase throughout age, so we were very interested in doing a comprehensive study with a large number of patients to define the prevalence of Ph-like ALL across the age spectrum of adulthood, and also to identify the underlying genetic lesions and see how they compare to those we had described in children and young adults,” said Mullighan, co-leader of the Hematological Malignancies Program at St. Jude Children’s Research Hospital.

The prevalence of Ph-like ALL across various age groups and the association with a worse outcome stimulates the need for more clinical trials to study ways to treat this subpopulation. To that end, the researchers explored the genetic landscape of adult patients with Ph-like ALL to find mutations and pathways that could be targeted with available therapies.

Of the 194 patients with Ph-like ALL in the study, genomic alterations activating kinase signaling were identified in 171 patients (88.1 percent). Of these, 99 patients (51 percent) had high expression of CRLF2, 25 of which also had a mutation of Janus kinases (JAK1/JAK2). The frequency of CRLF2 overexpression was highest among older adult patients at 58.4 percent compared with 51.1 percent in young adults and 46.8 percent in adult patients.

Alterations in kinase-activating genes identified included ABL class fusions in 9.8 percent of patients, that have not been recognized in B-cell ALL disease before: FIP1L1- PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA- EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B and KANK1-CBL1.

Alterations in cytokine receptor genes included sequence mutations of IL74, SH2B3, JAK1 or JAK3 and rearrangement of TYK2 in 7.2 percent of patients; Ras pathway mutations of KRAS, NF1, PTPN11 and CBL1 in 3.6 percent; and uncommon fusions, including FLT3, NTRK3, BLNK and PTK2B in 4.1 percent.

Rearrangements activating kinase signaling were found in 126 patients (65 percent) including 32 different rearrangements across 14 kinase or cytokine receptor genes. Further, 11 rearrangements were identified that have not been recognized in B-cell ALL disease before: FIP1L1- PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA- EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B and KANK1-CBL1.

The frequency of kinase fusions did not differ greatly between age groups, except for EPOR rearrangements, which were found more often in younger adults than in older adults.

Patients with a rearrangement of CRLF2, JAK2/EPOR, or ABL class genes were more likely to have a higher coefficient used in the classification of Ph-like ALL and were associated with a worse outcome. For patients harboring CRLF2 rearrangements, 68 percent were assigned a coefficient between 0.9 and 1, on the higher end of the spectrum, and 79 percent of patients with a JAK2/EPOR rearrangement had a coefficient between 0.9 and 1. Ninety percent of patients with an ABL-associated rearrangement had a coefficient between 0.9 and 1. However, patients with CRLF2 or JAK2/EPOR rearrangements were associated with worse 5-year EFS and OS rates than patients with ABL class rearrangements.

“This study confirmed that this is a prevalent form of leukemia, with similar kinase-activating genetic alterations to those previously described, but importantly, as we continue to sequence more cases, we find more lesions that we haven’t found before,” said Mullighan. “One of our key take-home messages from this study is that accurate management really needs accurate sequencing rather than just candidate testing approaches for the most common fusions.”

In the study, the authors suggested that the identification of patients with Ph-like ALL be incorporated in the design of future clinical trials.

In terms of potential treatment options, Ph-like ALL is characterized by a variety of genetic alterations in adults, most of which can be targeted by existing therapies, the study authors noted.

“In the context of these studies, the [most] promising approach is a TKI,” said Mullighan.

The study authors note that approximately 70 percent of the patients with Ph-like ALL could benefit from treatment with JAK inhibitors, such as Jakafi (ruxolitinib). Patients harboring CRLF2 rearrangements, JAK2/ EPOR rearrangements, and sequence mutations of JAK1, JAK3, IL7R or SH2B3, could all be treated with a JAK inhibitor.

Preclinical studies have shown the efficacy of Jakafi in Ph-like ALL or early T-cell precursor ALL. In a study of patient-derived murine xenograft models of ALL treated with the JAK1/2 inhibitor Jakafi, the treatment showed activity in all 6 of the xenograft models.

Patients harboring ABL1, ABL2, CSF1R, PDGFRA, or PDGFRB rearrangements could all benefit from being treated with ABL inhibitors, such as Gleevec (imatinib) or Sprycel (dasatinib), both of which have been approved for the treatment of patients with Ph-positive ALL.

In a previous study of Ph-like ALL, the researchers noted that cell lines and human leukemic cells in vitro expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive to dasatinib.

 Previous reports of patients with other tumor types expressing an ETV6-NTRK3 fusion have shown responses to the ALK inhibitor Xalkori (crizotinib).

“There are likely other forms of therapy that could treat this form of leukemia as well that are not necessarily related to the genetics,” Mullighan said. “But in terms of how these findings directly inform therapy, the implication is for TKIs... and inhibitors of ABL and JAK2 inhibitors are the 2 main agents moving ahead in to clinical trials. There are a number of other kinases as well that require other TKIs that are less commonly mutated or rearranged but are also very likely to respond and they’ll need to be tested in future work.”

Trials assessing the addition of TKI therapy to chemotherapy have commenced, including a trial studying the combination of Jakafi or Sprycel with chemotherapy in adult patients with Ph-like ALL (

There is a need for more targeted clinical trials for patients with ALL, since many of them have Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia. 

The Need for Targeted Clinical Trials in ALL

Previously treated patients with a rare subtype of melanoma had durable activity on Keytruda (pembrolizumab), according to data from three clinical trials presented at the 2017 European Cancer Congress in Amsterdam.

Patients with mucosal melanoma (84 patients) treated with Keytruda in the KEYNOTE-001, KEYNOTE-002 and KEYNOTE-006 studies demonstrated a median duration of response of 27.6 months.

These data are particularly important because they show that patients with this rare subtype of melanoma can benefit from anti—PD-1 therapy, said investigator Marcus Butler, M.D., in a statement.

“At this stage we don’t know why some mucosal melanoma patients responded to pembrolizumab, while others did not. This is an important question and research is ongoing,” Butler, of the Cancer Clinical Research Unit of the Princess Margaret Cancer Centre, explained.

In the three KEYNOTE trials, 84 of 1,567 patients (5 percent) had mucosal melanoma. Of these 84 patients, 57 percent were women, 49 percent were at least 65 years old, and 32 percent had an ECOG performance status of 1. Eight percent of the patients had 

 V600 mutations, 81 percent had M1c disease, and of the patients with known PD-L1 status, 70 percent had PD-L1—positive tumors.

All of the patients were previously treated; 90 percent of patients had received at least one prior therapy, and 8 percent had received more than three therapies. Thirty-nine percent of patients had previously been treated with Yervoy (ipilimumab).

Across the three KEYNOTE trials, patients received Keytruda at three different doses: 2 mg/kg every three weeks, 10 mg/kg every three weeks, or 10 mg/kg every two weeks.

The objective response rate (ORR) in the patients with mucosal melanoma was 19 percent with 16 patients responding, and the disease control rate (DCR) was 31 percent. The median progression-free survival (PFS) rate was 2.8 months and the median overall survival (OS) rate was 11.3 months.

“Sixteen of these patients (19 percent) responded to treatment with pembrolizumab, of whom 12 are still alive without their disease progressing and, so far, the longest time some of these patients have continued to be successfully treated is more than 27 months,” said Butler.

Of the patients previously treated with Yervoy, the ORR was 15 percent with five patients responding and the DCR was 27 percent. “Our results show that patients benefited from Keytruda regardless of whether or not they had been pre-treated with ipilimumab,” said Butler. In the three trials, patients with nonmucosal melanoma had an ORR of 33 percent and the DCR was 47 percent. The median PFS was 4.2 months and the median OS was 23.5 months.

In his presentation, Butler emphasized the impact that immunotherapy has had thus far on the treatment landscape of melanoma.

“Immunotherapy for melanoma has revolutionized treatment of the disease. There are some patients with mucosal melanoma who have had complete responses to Keytruda and essentially return to a normal life. Some, of course, have less spectacular responses, but they still benefit from therapy,” said Butler.

He added that earlier studies have previously excluded patients with mucosal melanoma, as it is a rare subtype of the disease.

“These findings suggest that mucosal melanoma patients should be offered immunotherapy as standard of care and not excluded. Response rates may be a bit lower than for other types of melanoma, so further studies to improve benefit need to be conducted,” he said.

“For rare cancer types, it is difficult to evaluate new treatments in normal sized trials. But here, Butler and colleagues pull three trials together and show that long-lasting responses also occur with pembrolizumab in patients with mucosal melanoma,” Peter Naredi, chair of the European Cancer Congress and president of the European Cancer Organization, said in a statement.

Three recent trials showed that Keytruda had a durable response for patients with a rare subtype of melanoma.

Keytruda Benefits Rare Melanoma Subtype in Three Trials

An increased clinical benefit was not seen when onartuzumab was added to Avastin (bevacizumab) for patients with recurrent glioblastoma multiforme (GBM), according to study results that were published in the 

However, patients with high hepatocyte growth factor (

 may derive clinical benefit from this combination regimen, Timothy Cloughesy, M.D., and colleagues noted in the study. Further research is warranted to validate these prognostic markers.

The phase 2 GO27819 trial assessed the safety and efficacy of onartuzumab added to Avastin, which received FDA approval in May 2009 as a single agent in the second-line treatment of patients with glioblastoma.

Exploratory biomarker analyses were also conducted in the study to identify an association between GBM subtype, 

 methylation and improved outcomes from the combination.

The phase 2 study randomized 129 patients 1 to 1 to either 15 mg/kg of onartuzumab once every three weeks plus 15 mg/kg of Avastin once every three weeks (64 patient) or Avastin with placebo (65 patients). Patients had recurrent disease after prior chemoradiation and had never received Avastin before.

An additional arm was originally included in the trial studying onartuzumab plus placebo, however, the cohort was placed on hold during a safety assessment.

Baseline patient characteristics were well balanced between the 2 arms of the study. The median age was 57 in the onartuzumab/ Avastin arm and was 55 in the Avastin/placebo arm. More than half of the patients (56.6 percent) had a Karnofsky performance score (PS) of 70 percent or 80 percent, and the rest had a PS of 90 percent or 100 percent.

After a median follow-up of 9.8 months for the onartuzumab arm and 9.9 months for the Avastin plus placebo arm, 92 percent and 85 percent of patients had discontinued treatment, respectively. The median progression-free survival (PFS) in the intention-to-treat population was 3.9 months with onartuzumab/ Avastin and 2.9 months with Avastin/placebo. The six-month PFS rate was 33.9 percent in the onartuzumab and Avastin arm versus 29 percent for the Avastin and placebo arm.

Median overall survival (OS) was 8.8 months versus 12.6 months for onartuzumab/ Avastin and Avastin/placebo, respectively. The objective response rate (ORR) was 22.2 percent in the onartuzumab arm, which included one complete response (CR), and the ORR in the Avastin and placebo arm was 23.7 percent, including three CRs.

General disorders of any grade occurred in 70.8 percent of patients in the onartuzumab/ Avastin arm and 57.8 percent in the Avastin /placebo arm, including peripheral edema (44.6 percent vs 14.1 percent, respectively), asthenia (24.6 percent vs 21.9 percent) and fatigue (15.4 percent vs 20.3 percent). Nervous system disorders were also common, experienced by 49.2 percent of patients in the onartuzumab group and by 75 percent in the Avastin group.

Grade 3 or higher adverse events (AEs) were noted in 25 patients (38.5 percent) in the onartuzumab/ Avastin arm and by 23 patients (35.9 percent) in the Avastin /placebo arm. A greater proportion of peripheral edema and hypoalbuminemia were both noted in the group receiving onartuzumab.

Two deaths occurred in the onartuzumab/ Avastin arm, both due to intestinal perforation, and one death occurred in the Avastin/placebo arm due to intracranial hemorrhage.

More patients had mesenchymal GBM (56 patients) than the proneural (28 patients) or proliferative (20 patients) subtype. No difference in PFS was noted with the mesenchymal subtype over the other subtypes, as had been seen in the AVAglio trial. Retrospective analyses of the AVAglio trial, which explored Avastin plus radiotherapy and temozolomide in GBM, had demonstrated a greater benefit for patients with mesenchymal or proneural GBM when receiving the Avastin combination, although only the proneural subtype showed a benefit in OS.

The AVAglio study also showed an association between the mesenchymal phenotype and expression of MET ligand HGF, which suggested “that this may be a common occurrence in glioblastoma biology,” the study authors noted.

In the GO27819 trial, high expression of 

 (upper 25 percent by polymerase chain reaction) seemed to be predictive of efficacy with the onartuzumab/ Avastin combination in patients with the mesenchymal subtype. Patients with higher 

 levels in the onartuzumab/Avastin arm had longer median PFS than patients in the Avastin/placebo arm of 6.1 months versus 2.8 months, respectively. The opposite was seen in patients with lower 

 methylation, a well-known prognostic marker in glioblastoma, was also explored among 47 patients with methylated 

 had better outcomes in the onartuzumab/Avastin arm, and multivariate analyses confirmed the potentially predictive effect of treatment with the combination for patients with unmethylated 

MET status was intended to be a part of the analyses, yet only five patients were MET-positive according to a greater than 50 percent staining cutoff by immunohistochemistry, which did not allow for a large enough population to study.

“Although the biomarker data are compelling and should inform future trials targeting the MET pathway, their exploratory nature and relatively small sample size make it difficult to infer firm conclusions on the clinical utility of HGF expression or MGMT methylation as predictive markers in glioblastoma,” the authors said in the study. “Future prospective studies are necessary to validate these results.”

The combination of onartuzumab and Avastin (bevacizumab) showed no additional benefit for patients with glioblastoma, according to a recent study.

Combo Shows No Additional Benefit in Glioblastoma

According to findings presented at the 2016 San Antonio Breast Cancer Symposium, women who are experiencing menopause symptoms are less likely to adhere to cancer treatments. Through clearer communication between the patient and health care staff, treatment concerns and the misattribution of menopausal symptoms to treatment side effects can be mitigated, said lead investigator, Samuel G. Smith, Ph.D.

“Communicating the likelihood of experiencing those symptoms is important,” said Smith, a Cancer Research UK postdoctoral fellow and university academic fellow at the University of Leeds. “What would be particularly interesting would be to look at all of the symptoms that were reported in trial arms [of this and similar trials] compared with placebo arms of each trial to look at what were naturally occurring symptoms and what were actually triggered by those particular therapies, and that way you can communicate more accurate information to patients so they can make an informed decision about whether or not they want to participate.”

Nine randomized trials have studied the effect of selective estrogen receptor modulators on the prevention of breast cancer, and have shown a reduction in the incidence of breast cancer by at least 30 percent, said Smith. In the IBIS-1 trial, extended analysis showed that five years of tamoxifen treatment can reduce the incidence of breast cancer for at least 20 years.

This analysis of patients enrolled in the IBIS-1 explored whether women experiencing menopausal symptoms were likely to adhere to their assigned treatment of tamoxifen or placebo for a period of 4.5 years.

Across both arms of the trial, 66.8 percent of women adhered to treatment, meaning that they remained on either tamoxifen therapy or placebo for 4.5 years. Women receiving tamoxifen (1,987 patients) were less likely to adhere to treatment than women in the placebo arm (2,000 patients) at a rate of 62.1 percent versus 71.5 percent, respectively.

Among women aged 35 to 70 at an increased risk of developing breast cancer in the United Kingdom, women experiencing menopausal symptoms including nausea/vomiting; gynecologic symptoms, such as irregular bleeding, vaginal dryness or vaginal discharge; headaches; and hot flashes were included in the analysis. Symptoms were assessed prior to trial entry and at six months.  

Characteristics were well matched across the two arms at baseline. The median age of the patients was 49 and a majority of patients had a family history of at least two family members affected by breast cancer. In each arm, patients had a median Tyrer-Cuzick risk of 5.7 percent of developing breast cancer.

Overall, symptoms of nausea/vomiting were experienced by 5 percent of patients, headaches by 7 percent, hot flashes by 31.5 percent and gynecologic symptoms by 20.9 percent. Most of these symptoms were mild, yet hot flashes at moderate levels were noted in 8.7 percent and at severe levels in 5.1 percent.

Of the women who reported nausea/vomiting, 53.7 percent adhered to either treatment and 58.6 percent of women reporting headaches adhered to treatment. Smith indicated that there was no relationship between hot flashes or gynecologic symptoms and adherence.

When stratified by trial arm, it was demonstrated that patients reporting nausea/vomiting in either arm of the trial were less likely to adhere to their assigned treatment, whereas patients reporting headaches who were receiving placebo were less likely to adhere to treatment, but this was not noted in the tamoxifen arm. Patients with gynecologic symptoms were less likely to be adherent in the tamoxifen arm, but not in the placebo arm.

“Tests of heterogeneity revealed that these effects of symptoms on adherence were comparable between the trial arms,” noted Smith.

Smith noted that increased interventions are needed to manage menopausal symptoms for women on these trials.

“Dropout rates were fastest within the first six to 12 months, indicating that this is an optimal time in which to deliver such interventions,” Smith said.

Moderator Kent Osborne, M.D., director of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, noted that while many methods now exist to ease these menopausal symptoms, most of these options—including venlafaxine HCI (Effexor) or other antidepressants to reduce hot flashes or acupuncture&mdash;were not known when the IBIS-1 trial was started over 20 years ago.

Perhaps recommending these methods for women experiencing menopausal symptoms could reduce the level of nonadherence to breast cancer prevention treatments.

Women who are experiencing symptoms of menopause often mistake those events as treatment side effects, leading to a decrease in adherence.

Menopause Symptoms Affect Treatment Adherence in Breast Cancer Survivors

A significant improvement in progression-free survival (PFS) was seen when Afinitor (everolimus) was added to Faslodex (fulvestrant) for premenopausal patients with metastatic hormone receptor (HR)—positive, HER2-negative breast cancer who are resistant to aromatase inhibitor (AI) therapy, according to findings from the phase 2 PrECOG 0102 trial presented during a press conference at the 2016 San Antonio Breast Cancer Symposium.

In the study, the Afinitor/Faslodex combination doubled median PFS rates compared with Faslodex alone, from 5.1 months on Faslodex to 10.4 months with the combination.

“We feel that the study provides additional evidence that adding everolimus to anti-estrogen therapy in AI-resistant disease improves clinical outcomes,” said Noah S. Kornblum, M.D., assistant professor of medicine, Albert Einstein College of Medicine, and attending physician of medicine, Montefiore-Einstein Center for Cancer Care.

The authors had hypothesized that the combination of Afinitor and Faslodex could be used to treat AI-resistant disease, which usually develops in most patients with HR-positive breast cancer treated with AI therapy. Researchers have shown that AI resistance can be overcome by targeting the PI3K-AKT-mTOR pathway, as seen in the phase 3 BOLERO-2 trial of Afinitor and Aromasin (exemestane) in patients with HR-positive advanced breast cancer and resistance to AI therapy.

In the BOLERO-2 trial, the addition of the mTOR inhibitor to Aromasin improved PFS rates from 3.2 months on Aromasin alone to 7.8 months with the combination. The combination was approved in 2012 for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer, largely based on results from the BOLERO-2 trial.

The patient population in the PrECOG trial were similar to those in the BOLERO-2 study, yet Kornblum believes that patients in the PrECOG placebo arm may have had longer PFS rates than those in the BOLERO-2 placebo arm due to the superiority of high-dose Faslodex over Aromasin.

“There are some potential advantages of fulvestrant in some people’s minds over steroidal AIs, such as exemestane,” Kornblum said. We don’t really have a direct comparison of these two combinations, but I think [fulvestrant and everolimus] does offer some [additional] options and it’s nice to have great options.”

Patients in the PrECOG trial were eligible if they had relapsed while on adjuvant AI therapy or had progressed after an AI therapy for metastatic disease, had an ECOG performance status score of 0 or 1, and had previously received no more than one chemotherapy regimen.

The 130 patients were randomized one-to-one in the induction phase to receive either high-dose Faslodex in addition to 10 mg of Afinitor or Faslodex with matching placebo. Patients continued treatment until progression or unacceptable toxicity for a maximum of 48 weeks. After 48 weeks, patients moved on to the continuation phase and could continue treatment of Faslodex with or without Afinitor.

The combination was associated with additional toxicity compared with the Faslodex-alone arm with grade 3 adverse events (AEs) occurring in 48 percent of patients in the combination arm versus 14 percent in the Faslodex group. The most common grade 3 AEs in the combination arm included stomatitis in 9 percent of patients, pneumonitis in 6 percent, fatigue in 5 percent and hyperglycemia in 6 percent.

The safety profile of the Afinitor/Faslodex combination was consistent with that of the Afinitor/ Aromasin combination in the BOLERO-2 trial. Yet Kornblum said that clinicians are all “learning on the fly, somewhat, how to manage the safety and toxicity profiles for these combinations.”

For instance, Kornblum noted that in the trial supportive care with prophylactic corticosteroid mouthwash was not used, which could have possibly prevented the frequency of cases of stomatitis as recent data has shown that the use of corticosteroid mouthwash reduces the risk of low-grade stomatitis. “That information was not known at the inception and conduction of this study,” he said.

A subset of patients with breast cancer saw an increase in progression-free survival with the addition of Afinitor to Faslodex. 

Progression-Free Survival Doubled With New Breast Cancer Combination

It is important to have a well-rounded understanding of the molecular and clinical causes and risks for patients with DNA mismatch repair deficiency (dMMR) rectal cancer, said Yi-Qian Nancy You, M.D., M.H.Sc., an author on a report published in the 

, which addressed gene alterations and treatment for patients with dMMR rectal cancer.

For patients with colorectal cancer, identification of dMMR triggers the need for genetic testing for the detection of a potential heritable germline deficiency in the DNA mismatch repair system. The implications of dMMR status are still unknown in rectal cancer, however, meaning that genetic testing has rarely occurred.

When genetic testing is performed on dMMR rectal cancer patients, a separation occurs between patients who present with mutations in their tumors in the mismatch repair system as well as the same mutations in the germline, and those who do not show the same mutations in the germline as can be found in their tumors.

Historically, this group has been clinically considered to have Lynch syndrome because there’s been no evidence to the contrary. Therefore, this subgroup of patients, along with their family members, would be considered to have a high lifetime risk of developing cancer and would subsequently require extensive screening.

“At some point when we figure out what’s going on with these people—what led to their tumor mutation if it’s not in the germline...then maybe we won’t need to keep them in this high-risk screening program and test them for all of these other Lynch-associated tumors,” said You, associate professor of Surgical Oncology, Division of Surgery, University of Texas MD Anderson Cancer Center, in an interview with 

However, this group, often termed “Lynch-like syndrome” by many reports, stands apart from those with Lynch syndrome. These patients have nonsporadic high microsatellite instability tumors, abnormal immunohistochemistry of the MMR proteins in the tumor, and no evidence of MLH1 hypermethylation or BRAF mutation. Also, genetic testing in these patients show various unclassified variants that are likely nonpathogenic, or results are inconclusive, whereas patients with true Lynch syndrome have identifiable pathogenic mutations. It is possible that these patients may not require as extensive screening as those with Lynch syndrome would.

One population-based study examined the risk of cancer in families of patients with “Lynch-like syndrome” in comparison with families of Lynch syndrome patients. The study found that the familial risk is reduced with Lynch-like syndrome compared with Lynch syndrome. The standardized incidence ratio (SIR) for colorectal cancer (CRC) for Lynch-like syndrome was 2.12 compared with 6.04 for classic Lynch syndrome. However, the SIR for Lynch-like syndrome was higher than the SIR for sporadic CRC of 0.48, confirming the need for surveillance of these families, although not to the extent of Lynch syndrome families.

The community does not yet have a consensus on not only how to manage these patients, but also regarding what to call this subgroup, commented You. She has proposed that these patients be termed “mutation-negative Lynch syndrome.” This phrase would differentiate these patients from the classic Lynch syndrome and nod to the fact that genetic testing shows unknown MMR genes in these patients.

The basis for “mutation-negative Lynch syndrome” needs to be understood in order to differentiate cancer treatment and surveillance for these patients and their family members. You and colleagues’ study of dMMR in rectal cancer aimed to begin to identify the molecular basis of this patient population compared with Lynch syndrome patients, and to begin to identify which treatment would most benefit these patients.

In the study a selection of 62 patients over the age of 18 years old with dMMR rectal adenocarcinoma, who were diagnosed between 1992 and 2012, were tested for tumor MMR status, microsatellite instability, and immunohistochemistry of the MLH1, MSH2, MSH6 and PMS2 proteins.

Patients with detected deficiency in MLH1, MSH2, MSH6 or PMS2 underwent genetic counseling for confirmatory germline mutation testing. Forty-two patients had true Lynch syndrome and 15 patients had mutation-negative Lynch syndrome, seven of which had presented with a variant of unknown significance (VUS), all of which were missense mutations and eight had uninformative negative results. The remaining five patients had declined genetic testing.

Ninety-eight percent of the patients met the revised Bethesda criteria while only 15 percent met Amsterdam criteria 1 or 2. The median PREMM 1,2,6 score for all of the patients was 25.6.

Following testing, it was found that a majority of the patients had a mutation in either MSH2 (53 percent) or MSH6 (23 percent). Expectations had favored the MLH1 gene for the majority of defects in MMR, study authors noted in a statement, as this is commonly found in patients with dMMR colon cancer. However, only 16 percent of patients in the study had a mutated MLH1 gene and 8 percent had a mutation in PMS2.

Thirty of 40 patients (75 percent) with stage 2 or 3 rectal cancer were treated with neoadjuvant uoropyrimidine-based chemotherapy and long-course pelvic radiation. All but one of these patients underwent surgical resection. Eight patients (27.6 percent) experienced a pathological complete response and 16 patients (55.5 percent) were downstaged following treatment.

For the entire patient population, the five-year overall survival (OS) rate was 87 percent and the rectal cancer-specific survival (RC-SS) rate was 90.6 percent overall. For patients with stage 1 and 2 disease, the RC-SS rate was 100 percent, 85.1 percent for stage 3, and 60 percent for stage 4. Recurrence occurred in 18.6 percent (11 of 59) of the patients who had curative-intent resection. Eleven of the patients died, six due to rectal cancer and five due to extracolorectal cancers after a median of 17.3 years. Although all of the patients with VUS mutation-negative Lynch syndrome were still alive as of last follow-up.

Fourteen patients (22.6 percent) developed a total of 22 extra-colorectal cancers. Study authors noted that the MSH2 and MSH6 MMR genes have been associated with higher incidences of extracolorectal cancers.

“Our data basically established what the results are with current therapy. That provides a baseline for developing trials that include new drugs because you have to have something to compare it against to see whether the new drugs are going to add any benefit,” You said.

Future trials may examine the effect of immunotherapy and targeted therapy agents on patients with dMMR rectal cancer. You noted that clinical trials are already underway examining PD-1 blockade in tumors with DNA dMMR, which have already shown substantial results. It is suggested that dMMR is predictive of response to immune checkpoint blockade treatment.

The trial also provides implications for the underlying genetics of dMMR rectal cancers. “Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies,” the study authors emphasized in their abstract.

In dMMR colon cancers, genetic testing is more common right off the bat to identify patients with Lynch syndrome. However, dMMR is different in rectal cancer than in colon cancer, You pointed out.

“We think if you find rectal cancer, the likelihood that someone is actually Lynch is much, much higher than if it’s a colon cancer because there are other ways of causing it in colon cancer. The other known mechanisms that cause tumor dMMR we can’t find in rectal cancer.”

Subsets of colon cancers that develop DNA dMMR are caused by other mechanisms, such as hypermethylation of a gene, typically MLH1. On the other hand, there is no methylation or other known mechanisms causing the deficiency in rectal cancer patients. The causes are still unknown for rectal cancer.

In the meantime, there is a better indication of the long-term prognosis of these patients. The long-term multiorgan follow-up of patients with dMMR rectal cancers is very important, You urged, especially since many will develop extracolonic cancers as their germline mutations put them at a lifelong risk for developing other cancers.

This follow-up extends beyond the patient to members of their family as well. Once a patient has been diagnosed with a genetic mutation it can affect the entire family as they will all need to be continually screened for associated cancers.

“Precision medicine is good for this one patient, of course, but it’s so much more powerful if you think of the implications for all of the generations,” You said.

Patients with DNA mismatch repair deficiency rectal cancer may not necessarily have Lynch syndrome. Expert Yi-Qian Nancy You weighs in on the topic.