The OBR Blog

May 17, 2017 - 09:05 pm comments0 Comments

It's ASCO time again! As the 2017 Annual Meeting of ASCO rolls around, a pre-meeting presscast was held to highlight 6 abstracts of importance. The topics included the positive impact of lifestyle interventions on survival in colorectal cancer (CRC), delaying recurrence with adjuvant gefitinib in EGFR-positive non-small-cell lung cancer (NSCLC), adjuvant capecitabine as a new standard of care for biliary tract cancers, and two epidemiology studies: one on the positive impact of human papillomavirus (HPV) vaccination on the prevalence of oral HPV infection, and another showing that the Affordable Care Act has led to increased cancer diagnoses at earlier stages of disease when they are treatable.

Lifestyle Changes and CRC

A healthier lifestyle appears to improve survival in CRC, according to two prospective studies. Eating more tree nuts (but not peanuts or peanut butter) was associated with reduced risk of recurrence and death for patients with stage III CRC. This prospective study included 826 patients with stage III CRC who reported on dietary intake with food frequency questionnaires as part of a randomized adjuvant chemotherapy trial. Compared with patients who abstained from nuts, those who ate at least 2 servings of nuts per week were 42% more likely not to recur and 57% more likely not to die. Lead author was Temidayo Fadelu, MD, Dana-Farber Cancer Center, Boston.

A second prospective study of the same cohort of patients enrolled in the randomized adjuvant chemotherapy trial found that CRC patients who followed the 2012 American Cancer Society (ACS) Nutrition and Physical Activity Guidelines (maintaining a healthy weight, being physically active 1 hour a day 5 days a week, eating a healthy diet rich in fruits and vegetables and whole grains) had prolonged disease-free survival (DFS) and overall survival (OS) compared with patients who did not adopt these behaviors.

Over a median follow-up of 7 years, 335 patients recurred and 299 died. Patients completed behavior surveys at baseline and at 6 months. Patients who had a score that showed good adherence to the ACS guidelines had a 42% lower risk of recurrence and death. When moderate intake of alcohol (1 drink per day for women; 2 drinks per day for men) was factored in, patients with good adherence to the ACS guidelines had a 68% reduced risk of recurrence and death. Lead author was Erin Van Blarigan, ScD, UCSF, California.

"Both studies show that we can be optimistic for patients with early stage CRC. Chemotherapy and surgery can improve overall survival and there is a pretty good chance of surviving if patients maintain a healthy lifestyle," said ASCO President Daniel E. Hayes. Dr. Hayes stressed that these findings do not suggest that patients with early stage CRC should forego standard treatment with chemotherapy and surgery.

"The fact that these were prospective observational studies removes the inherent bias of retrospective studies that rely on memory," Dr. Hayes added. "This makes these findings more compelling."

Adjuvant Gefinitib

EGFR-tyrosine kinase inhibitors (TKI) are standard first-line treatment for EGFR-mutated advanced lung cancer. Adjuvant EGFR-TKI targeted therapy with gefinitib (used earlier in the course of disease) delayed recurrence compared with standard cisplatin-containing chemotherapy in a randomized, Phase 3 trial of 220 patients with stage II-IIIA, EGFR-positive, completely resected NSCLC. Patients who received daily gefitinib for 24 months had a significantly longer disease-free survival (DFS) compared with those treated with 4 cycles of standard chemotherapy: 28.7 months vs 18 months, respectively (P=.005). Adverse events, including Grade 3 and 4, were more frequent in the chemotherapy arm.

This is the first randomized trial to compare these two therapies in patients with EGFR mutations. Results suggest that gefitinib should be considered as an important option for this group of patients, and that routine EGFR testing should be considered in these earlier stage lung cancers, according to lead author Yi-Long Wu, MD, Guangdoong Lung Cancer Institute, Guangdong General Hospital, Guangzhou, China.

ASCO President-Elect Bruce Johnson, MD, said, "The disease-free survival was superior for gefitinib in this trial, but ultimately we are interested in the survival results [before we change practice]. Dr. Wu is planning a survival analysis and I will follow that closely."

Richard Schilsky, MD, ASCO spokesperson, said that EGFR testing is typically done at later stages of NSCLC. "If this turns out to be a treatment option, we will begin testing for EGFR earlier in the course of disease."

Adjuvant Capecitabine

Adjuvant capecitabine extended OS by a median of 17 months compared with surgery alone in patients with biliary tract cancers (occurring in bile ducts inside and outside of the liver and gallbladder). From March 2006 to December 2014, the study randomized 447 patients to capecitabine for 6 months or observation. More than 80% of patients were monitored and followed for 3 years after surgery. Median survival was 51 months in the capecitabine group vs 36 months in the observation group, reflecting a 20% lower likelihood of death, which was not significant in an intent-to-treat analysis (P=.097). However, a per protocol analysis found a statistically significant 25% reduction in death for capecitabine vs observation (53 months vs 36 months; P=.028).

Toxicity was relatively modest with little difference in quality of life between the two arms.

"This is the first trial to enroll a sufficient number of patients to show that chemotherapy after surgery can have a significant improvement in survival with modest side effects, and should be a new standard of care," said John N. Primrose, MD, Professor of Surgery at the University of Southampton, U.K.

"This is an impressive study that represents an enormous amount of work. Biliary tract cancer is more common in Asia than in the Western world and we don't know if these results are generalizable to Asia," said Dr. Hayes .

HPV Vaccination

Although it is well known that the HPV vaccine can prevent the development of HPV-positive cancer, vaccine uptake in the U.S. is suboptimal. One of the first large studies to evaluate the impact of HPV vaccine on oral HPV infection (a risk factor for oropharyngeal cancer) showed that the prevalence of high-risk HPV infection was 88% lower among young adults in the U.S. who reported getting at least 1 vaccine dose than among those who were not vaccinated.

"Rates of HPV-caused oral cancers continue to rise every year in the U.S., particularly among men. And yet, no clinical trial has evaluated the potential use of the HPV vaccine for the prevention of oral HPV infections that could lead to cancer," said senior study author Maura L. Gillison, MD, PhD, now professor at the University of Texas MD Anderson Cancer Center in Houston. Dr. Gillison led this research when she was at Ohio State University.

The study was based on 2627 young adults ages 18-33 during the period 2011-2014 who were part of the National Health and Nutrition Examination Survey (NHANES) from 2009 through 2016. An important finding was that fewer than 1 in 5 young adults (18.3%) received at least 1 dose of the vaccine before age 26. The vaccine rate was only 6.9% among males vs 29.2% among females.

Prevalence of oral HPV infection was lower among vaccinated people vs unvaccinated people: 0.11% vs 1.61%, respectively (P=.008), for an 88% reduction in prevalence. Among men, the prevalence of oral HPV infection was zero in those vaccinated vs 2.1% in the non-vaccinated group (P=.007).

Because of the low uptake of the vaccine in at-risk youth, only a modest effect of the vaccine could be shown on the prevalence of the types of oral HPV infections covered by the vaccine. With current uptake rates, the vaccine reduced the prevalence of vaccine-covered, oral HPV infections by 17% in the overall general population.

"This vaccine has tremendous potential to prevent oral HPV infection associated with cancer. It is estimated that if 1 million people had this vaccine, it could prevent more than 900,000 from having oral HPV infection," stated Dr. Gillison .

ASCO President-Elect Bruce E. Johnson, MD, FASCO stated: "The HPV vaccine has the potential to be one of the most significant cancer prevention tools ever developed, and it's already reducing the world's burden of cervical cancers. The hope is that vaccination will also curb rising rates of HPV-related oral and genital cancers, which are hard to treat. This study confirms that the HPV vaccine can prevent oral HPV infections, but we know it only works if it's used."

Cancers Diagnosed Earlier

More cancers were diagnosed earlier at a more treatable stage after full implementation of the Affordable Care Act (ACA) in 2014. An analysis of about 273,000 patients showed a 1% increase in the percentage of breast, lung, and colorectal cancers diagnosed at the earliest, most treatable stage between 2013 and 2014. This small percentage represents a significant number of new cases and could potentially lead to improved outcomes.

Lead author Huesong Han, PhD, Strategic Director of Health Policy and Healthcare Delivery Research at the American Cancer Society, said: "Although we only analyzed data from a limited timeframe, the fact that there appears to be a positive trend in diagnosis at an earlier stage in these common cancers is encouraging."

The percentage of patients diagnosed with prostate cancer at earlier stages did not increase, and the authors attributed this to the USPSTF recommendation against routine PSA screening in the general population.

by Adrian Barfield

April 24, 2017 - 11:04 pm Posted in AACR Conference Coverage comments0 Comments

Carlo Croce, MD, FAACR, is the recipient of the 2017 AACR Margaret Foti Award for Leadership and Extraordinary Achievements in Cancer Research, presented to him at the 2017 AACR Annual Meeting. Dr. Croce, a leading researcher in cancer genetics, has won many awards over the duration of his career and is particularly proud to receive this one.

"What makes this award different from the others I have received is that is in the name of Margaret Foti, who is CEO of AACR. I have known Margaret for many years and watched her help shape the growth of AACR to become the organization that it is now. Margaret has always pushed for better cancer research. When I started my career, AACR was a small organization. Now the AACR Annual Meeting is the most important meeting for cancer research in the world. You will hear about the latest fundamental [basic], applied, and clinical research at this meeting.  Even the poster session is exciting," Dr. Croce told OBR.

Dr. Croce is director of the Institute of Genetics and director of the human cancer genetics program at The Ohio State University Comprehensive Cancer Center, and professor and chair of the Department of Molecular Virology, Immunology, and Medical Genetics at The Ohio State University School of Medicine in Columbus.

Margaret Foti, PhD, MD, said: "Dr. Croce is a highly esteemed basic and translational cancer researcher whose paradigm-shifting work has provided the basis for intensive investigations throughout the international scientific community. He has also provided extraordinary scientific leadership in the national and international scene, including research administration and mentorship of many talented young investigators, and he is greatly deserving of this award."

Among Dr. Croce's achievements is establishing the genetic links to a variety of cancers, including Burkitt lymphoma, T-cell lymphoma, and acute leukemia. His studies have shown that chromosomal abnormalities such as translations are capable of contributing to both cancer initiation and progression. He was the first investigator to discover and sequence BCL-2. More recently, his studies have focused on understanding the role of micro RNAs in cancer pathogenesis, including the potential for oncogenic or tumor suppressive properties.

When asked what he is particularly excited about right now, Dr. Croce said: "I am a cancer geneticist and I am excited about the whole field. Some people think cancer genetics is dead, but this is far from true. The more we understand about cancer genetics, the more we realize how complex this whole field is. For example, if we could better understand cancer initiation, we could find novel ways to treat cancer."

"We have a lot to learn. Only after we discover what all the changes in cancer genomics mean will we learn to treat cancer well. At first, we thought sequencing the genome would be the end-all, but this is the beginning. We have made much progress, but we need to continue to support more basic research to move forward and have better cancer treatments."

Dr. Croce is a lucky man for many reasons, not the least of which is his enduring passion for his work.
"I go to work with pleasure every day," he told OBR.

By John McCleery

April 18, 2017 - 05:04 pm Posted in AACR Conference Coverage comments0 Comments

Immunotherapy pioneer Carl June, MD, was named member of the 2017 class of fellows of the American Association for Cancer Research (AACR) Academy in April 2017, in recognition for his pivotal role in designing chimeric antigen receptor T cell immunotherapy (CAR-T) for the treatment of relapsed/refractory chronic lymphocytic leukemia.

Dr. June is director of the Center for Cellular Immunology in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at University of Pennsylvania School of Medicine.

When asked by OBR what this award means to him, Dr. June replied: “The AACR fellowship was a very special award for several reasons. First, the previous inductees are in many cases my most revered colleagues and mentors, who are literally the 'Who’s who' of cancer research. Secondly, the induction ceremony led by AACR leadership was very special.”

Dr. June began his research on genetically modified T cells in the 1990s when he was studying HIV/AIDS. This work led to his studying this technology in leukemia and the first clinical trials in leukemia patients in 2010. At that time, only three cancer centers had open CAR-T trials; now more than 110 CAR-T trials are open in the U.S. and other countries.

CAR-T cell therapy is still a work in progress. Although this therapy has achieved dramatic results in some patients with no other treatment options, it can also unleash the immune system to go awry, so much attention has focused on optimizing outcomes while taming unwanted immune responses.

The first pediatric patient to receive CAR-T therapy was Emily Whitehead, a 7-year-old child with intractable, seemingly fatal acute lymphoblastic leukemia. Her miraculous recovery made front-page headlines and she is alive and in remission at age 10.

Since then, scores of other patients with leukemias and other hematologic cancers have received CAR-T, with excellent and unprecedented remissions in many patients. The therapy is furthest along in development for the treatment of acute lymphocytic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma, and approval by the FDA is expected sometime in 2017.

CAR-T is also investigational in multiple myeloma and acute myeloid leukemia and in some sold tumors.

Dr. June continues his research on CAR-T and how best to exploit this novel approach. “The fundamental goal of CAR-T research is to contribute to the ultimate solution for cancer: curing and preventing,” he told OBR.

By John McCleery

February 13, 2017 - 10:02 pm Posted in ASCO GU Conference Coverage Posted in Kidney (Renal Cell) Cancer Posted in Prostate comments0 Comments

The 2017 Genitourinary Cancers Symposium takes place in Orlando, FL, on February 16 – 18, and a press cast held in advance of the meeting featured 3 important abstracts, with these key findings:

  • For patients with metastatic renal cell carcinoma, response to immunotherapy — specifically anti-PD-1/PD-L1 agents — may remain durable even if the drugs are discontinued early due to side effects
  • Also in patients with metastatic renal cell cancer, receipt of antibiotics within 1 month of starting immunotherapy may render checkpoint inhibitors less effective
  • Liquid biopsy in patients with advanced prostate cancer can reveal multiple genetic alterations in cell-free circulating tumor DNA (ctDNA) — this approach is simpler than traditional tissue biopsy and could identify new treatment targets for patients whose disease is progressing

Early Discontinuation of PD-1/PD-L1 Blockers May Not Compromise Efficacy

In a small study of 19 patients with metastatic renal cell carcinoma (RCC), discontinuation of anti-PD-1/PD-L1 immune checkpoint inhibitors due to side effects did not always lead to poor outcomes. The findings may challenge the current practice of continuing these drugs until (and sometimes after) the patient’s disease progresses.

Among 19 patients who initially responded to nivolumab but discontinued because of immune-related side effects, 42% had a durable response lasting for 6 months or longer, according to Rana R. McKay, MD, of the University of California San Diego School of Medicine.

“In medicine, we are constantly balancing the benefits and risks of any given treatment. This is a small study, and our findings need to be validated in a larger group of patients, but it underscores that in some cases, immunotherapy can have lasting benefits even after treatment discontinuation,” she said.

Two thirds of patients had received nivolumab as a single agent and the remainder received it in combination with other systemic treatments. The median time on immunotherapy was 5.5 months. All 19 discontinued treatment because of immune-related side effects, such as joint pain, rash, eye problems, diarrhea, and inflammation of the pituitary gland, muscle, heart, liver, pancreas, kidney or lung. Steroids were administered to 84% of patients and additional immunosuppressive agents were required for 11%. More than half the group had ongoing toxicity at the time of the analysis.

In 3 (16%) patients, the tumor progressed immediately after stopping treatment, but 8 (42%) patients had a continued response after being off treatment for at least 6 months. The remaining 8 (42%) were off treatment for 4 to 6 months or had follow-up for less than 6 months. The durable responders spent a median of 11 months on treatment and 20 months off treatment, reported Dr. McKay.

“We demonstrated that responders to anti-PD1/PD-L1 agents can have persistent clinical benefit despite treatment discontinuation for immune-related adverse events,” said Dr. McKay.

The prospective OMINIVORE study (Phase 2 study of Optimized Management of NIVOlumab based on Response) will further explore the efficacy of immunotherapy treatment discontinuation in treatment responders.

Press cast moderator and ASCO Expert Sumanta Pal, MD, reiterated the study’s message: that while the “unintended consequences of a reinvigorated immune response,” ie, immune-related adverse events, can be “serious,” patients with these side effects “can still have tangible benefit from these drugs.”

Recent Antibiotic Use May Negate Immunotherapy Benefits

In a retrospective analysis, patients with metastatic RCC who were treated with antibiotics within 1 month of starting treatment with immune checkpoint inhibitors had a significantly shorter progression-free survival, versus patients not taking antibiotics, according to French investigators.

The researchers attribute this to the ability of antibiotics to wipe out “good bacteria” in the gut, based on preclinical studies showing that certain microorganisms in the gut interact with the immune system in a way that facilitates the effect of immune checkpoint inhibitors.

The study is the first to analyze the impact of antibiotics on immune checkpoint inhibitors, and provides the first evidence of a relationship between the gut microbiome and patients’ response to immunotherapy.

The study included 80 patients with metastatic RCC enrolled in a trial of anti-PD-1/PD-L1 agents. Of these, 16 (20%) had been treated with broad-spectrum antibiotics (mostly beta-lactamases and fluoroquinolones) from baseline up to 1 month prior to the first injection.

Compared with patients not taking antibiotics, antibiotic users had significantly worse progression-free survival: 2.3 months vs 8.1 months, respectively (P< .001); their response rates to the checkpoint inhibitors were also lower.

This statistical association was maintained in a multivariate analysis that adjusted for age, gender, disease risk group, tumor burden and use of proton pump inhibitors. Antibiotic users’ risk for progression was increased more than four-fold vs non-users.

“Although it’s too early to conclude about overall survival, with median follow up of less than 6 months, there is already a negative trend in the antibody-positive group,” reported Lisa Derosa, MD, MD, a PhD candidate at the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Dr. Derosa suggested that the findings may be applicable to other tumor types, since antibiotics are frequently used in cancer patients in general to prevent and treat treatment-related infections. At this time, she does not recommend withholding antibiotics from patients taking checkpoint inhibitors.

Dr. Pal agreed, stating, “While Dr. Derosa’s findings are very intriguing, they were retrospectively generated and therefore are hypothesis-generating. Having said that, the observations are consistent with preclinical observations. With further prospective validation, we may gain insight as to whether the bacterial composition of the gut affects clinical outcomes, and this could help guide us in our antibiotic usage. Meanwhile, we must consider that antibiotics are used under circumstances that are medically necessary.”

In Prostate Cancer, Liquid Biopsy Reveals Potential New Treatment Targets

Analysis of cancer DNA from blood samples is yielding some new leads for potential prostate cancer treatment targets. With a commercially available liquid biopsy — which examines cell-free circulating tumor DNA (ctNDA) in the bloodstream — researchers identified new genetic mutations in prostate cancers, some of which were associated with poor prognosis.

Cell-free DNA reveals a tumor’s genetic profile, for which targeted treatments can be designed. The genetic landscape, however, changes over time, rendering some drugs ineffective because resistance develops.

If the ctDNA can identify the evolving mutations, clinicians could discontinue futile treatments and switch therapies, explained Guru Sonpavde, MD, of the University of Alabama in Birmingham.

The study included blood samples from 514 patients with metastatic castration-resistant prostate cancer (mCRPC). The test, Guardant360, examined changes in 73 cancer-related genes.

In 163 patients, researchers explored associations between DNA changes and clinical outcomes, and in 64 patients they documented genetic changes over time through serial testing.

“Almost all the patients (94%) had some change detected, and most changes were associated with worse poor outcomes,” reported Dr. Sonpavde.

Higher number of ctDNA alterations was associated with shorter time to treatment failure (P=0.026). Patients with prior treatment for mCRPC had significantly more alterations in the androgen receptor gene (AR) than untreated patients (56% vs 37%; P=0.028).

Genes most often mutated were TP53, AR, APC, and NF1. Increased copy numbers were most common with AR, MYC and BRAF; increased cancer gene copy number can lead to proliferation of proteins that drive tumor growth.

Serial testing revealed that changes in AR over time were common. Importantly, patients with these mutations also trended toward shorter remissions (P=0.053) and shorter survival time (P=0.09).

“This indicates that developing salvage therapy with agents targeting AR alterations holds promise,” commented Dr. Sonpavde.

The findings via ctDNA were consistent with changes observed through traditional tissue biopsy, suggesting that noninvasive liquid biopsy may be a viable alternative.  While there are currently no approved drugs targeting the most common mutations observed, some are in clinical trials noted investigators.

Dr. Sonpavde acknowledged that a controlled, prospective clinical trial is needed to confirm that treatment based on the molecular information from ctDNA improves patient outcomes.

Dr. Pal remarked that the study offers “one of the largest clinically annotated datasets describing features of ctDNA in advanced prostate cancer, which is a simple and convenient way to assess DNA composition and can reveal new mutations that clinicians can use to personalize therapy… The development of new agents targeting the androgen receptor is a good future direction of research.”

John McCleery

 

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