AACR 2019 Show Preview: Integrative cancer science meets individualized care

Over 20,000 attendees will converge on Atlanta this year for the 110th AACR Annual Meeting

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The American Association for Cancer Research (AACR) heads to Atlanta, where it will host its 110th Annual Meeting from March 29 to April 3 at the Georgia World Congress Center. The AACR Annual Meeting 2019 has an anticipated attendance of more than 22,500 scientists, clinicians, advocates and other attendees from around the world, and brings together what AACR call “the best talent and job opportunities in cancer and biomedical research.”
“The AACR Annual Meeting program covers the latest discoveries across the spectrum of cancer research—from population science and prevention; to cancer biology, translational and clinical studies; to survivorship and advocacy—and highlights the work of the best minds in research and medicine from institutions all over the world,” says AACR’s meeting website.
“The AACR annual meeting is the meeting that we all look forward to very year,” says Dr. Elizabeth M. Jaffee, AACR’s 2018-2019 president, in a welcome/preview video for the meeting. “It’s a meeting that brings experts from all sectors of the cancer community—from government, academia, the pharmaceutical industry, survivorship, patients, patient advocates. It brings everyone together at one meeting. It’s a huge meeting. The best science—the most up-to-date science—is presented, from basic to translational to clinical care.”
With this year’s theme, “Integrative Cancer Science • Global Impact • Individualized Patient Care,” the scientific program includes a roster of world-class speakers, hundreds of invited talks and more than 6,000 proffered papers. Presentations at the AACR Annual Meeting will span the entire field of cancer research, highlighting basic, translational and clinical research on important topics such as immunotherapy, science policy, targeted therapy, artificial intelligence, liquid biopsy, early detection, cancer interception, prevention, survivorship and cancer health disparities. This year’s meeting will also include a number of science policy sessions. Those following the meeting on social media can join the conversation on Twitter with the hashtag #AACR19.
“At this year’s AACR annual meeting in Atlanta, there will be an extensive focus on the science of cancer health disparities, including a plenary session dedicated to this important topic,” says Dr. John D. Carpten, the 2019 program chair for the AACR meeting, in AACR’s welcome/preview video. “In addition, we will offer a wide range of educational and scientific sessions covering the entire spectrum of cancer health disparities and research.”
As Jaffee told DDNews, AACR added a new session format this year, and two special sessions on “Making Science Count for Patients” will focus the story of basic science discoveries that led to translational research and clinical application. “One session will have talks covering the discovery of cytotoxic T cell antigen (CTLA)-4 as a modulator of T cell co-stimulation through to the clinical application and development the anti-CTLA-4 antibody,” she says. “The other session will focus on CDK4/6.”
Jaffee also points out that AACR has added a drug development track to this year’s program. Moreover, “This year we have increased the number of NextGen Stars speaking opportunities. In addition to being integrated into some thematic major sessions, we have two dedicated spotlight sessions to highlight the work of these rising stars.” (See also the “NextGen Stars” sidebar below.)
The AACR Annual Meeting Online Program Planner is currently available so that users can browse and search all sessions and presentations by author, title, session type or track/organ site. Meeting registrants will be able to log in and create a personal itinerary.
“The AACR is the oldest and largest scientific organization in the world, focused on every aspect of high-quality, innovative cancer research. Its reputation for scientific breadth and excellence attract the premier researchers in the field,” notes AACR’s website. “The programs and services of the AACR foster the exchange of knowledge and new ideas among scientists dedicated to cancer research, provide training opportunities for the next generation of cancer researchers, and increase public understanding of cancer.”
Or, as Jaffee elaborates in the welcome/preview video: “We get to network with individuals that it’s hard to meet with at other times in the year. You get to network with groups that you may be collaborating with, you get to network with groups where you can form new collaborations. You get to interact with young people—young people who are interested in cancer research; who may be interested in coming and working in your laboratory someday or may be interested in their first job with you. So it’s just an opportunity for the whole community internationally to get together, network, interact, share information—and the hope is that by doing this, we’re really making big progress in the future of cancer research.”
Another new feature of this year’s meeting is an additional day of educational programming, which will begin on Friday, March 29, at 3 p.m. and continue through Saturday, March 30. More than 60 unique Educational Sessions and Methods Workshops are included in this program, and sessions are open to all meeting registrants. The Opening Ceremony and the Opening Plenary Session will take place on Sunday morning, March 31.
“Don’t miss this opportunity to join more than 23,000 of your colleagues from around the globe in order to network with the greatest minds in cancer research,” urges Carpten.

Educational Sessions and Methods Workshops
Education Sessions
Friday, March 29
  • Biomarker Studies: Study Design and Statistical Considerations
  • Genetic Predispositions to Childhood Leukemias: Implications for Pathogenesis and Screening
  • Host versus Tumor Autophagy in Cancer
  • Immune-Targeted Biomarker Incorporation into Therapeutic Decision Making
  • Integrating Tumor Immunology and Molecular Epidemiology
  • Intersection of Radiation and Immune Therapy
  • Modulation of the Gut Microbiome to Treat Dysbiosis and Cancer
  • Molecular Pathology for Cancer Researchers: Present and Future
  • Preleukemia and Clonal Hematopoiesis
  • Quantitative Approaches to Study Cancer Evolution and Heterogeneity
Methods Workshops
Friday, March 29
  • Controversies in Replication cfDNA Measurements
  • Defining Tumor Organ-systems with Single Cell Transcriptomics
  • Game-Changing Technologies for High Through-Put Functional Characterization of Cancer Gene Variants
Education Sessions
Saturday, March 30
  • Cancer Genomic Reference Samples: MDIC Somatic Reference Sample Collaborative Initiative
  • CAR-T Therapy State of the Art
  • Characterizing Cancer Disparities Nationally and Internationally Using Publicly Available Data: Recent Advances
  • Chemistry to the Clinic: Part 1: Lead Optimization in Cancer Drug Discovery
  • Chemistry to the Clinic: Part 2: Novel Chemical Tools and Leads for Unprecedented Targets
  • Chemistry to Clinic: Part 3: Unconventional Modalities to Extend the Antitumor Target Space
  • Co-evolution of Tumor and Microenvironment in Cancer Metastasis
  • Convergence
  • CtDNA for Cancer Stratification, Monitoring, Clonal Tracking, MRD Detection, and Early Diagnosis
  • Developing Standardized Platforms for Immune monitoring in Cancer Immunotherapy Clinical Trials
  • Diverse Functions of Neutrophils in Cancer
  • East Looks West: Chinese Pharma Explodes Western Markets
  • The Endothelium and Fluid Flows: Linking Metastasis and Immunity
  • The Evolution of the Art and Science of Go/No Go Decisions in Cancer Drug Development
  • Extracellular Vesicles and Intercellular Communication in Cancer
  • Fibroblasts in the Driver’s Seat: Impact on Tumor Progression and Therapy Resistance
  • Fluorescence Image-Guided Surgery for Improved Clinical Outcomes
  • From Cancer Genomics to the 3D Organization of the Genome
  • Functional Follow-Up of Microbiome Associations for Cancer Epidemiology Studies
  • Impact of a Brexit on Oncology Drug Development and Regulation
  • Making Your Voice Heard: How to Effectively Advocate for Cancer Research and Science-based Policy
  • Metabolic Drivers of Cancer
  • Molecular Regulation of Cancer Inflammation, Progression, and Treatment Resistance
  • Obesity: The Effects of Local and Systemic Inflammation on Cancer
  • Oncolytic Virus Therapy
  • Ordering Genomic Changes as Actionable Targets in Pediatric Cancers
  • Organoids as Model Systems in Cancer
  • Pancreatic Tumor Microenvironment
  • Personalized Circulating Tumor DNA Analysis for Minimal Residual Disease Detection
  • Precision Medicine in 2019
  • Resistance to Therapies and Cancer Cell Dormancy
  • Single-Cell and Spatial Genomics
  • Stromal Niches for Organ-Tropic Metastasis
  • Systems Biology Approaches to Cancer
  • Targeting Cancer Neoantigens
  • Tools for Machine Learning in Cancer Image Analysis
  • Tumor Immunology and Immunotherapy for Nonimmunologists: Roundtable Discussions
  • Tumor Immunology and Immunotherapy for Nonimmunologists: Standard Cancer Therapies are Ultimately Immunotherapies
  • Update on Young Women’s Breast Cancer
  • Vascular-Immune Cell Cross-Talk: Implications for Cancer Immunotherapy
  • West Looks East: Western Pharma Explores the China Mainland
Methods Workshops
Saturday, March 30
  • BRCA1 Variants of Unknown Significance (VUS): New Vistas in the Assessment of Cancer Risk
  • Clinical Trial Design: Part 1: The ABCs of Doing Cancer Clinical Trials
  • Clinical Trial Design: Part 2: Novel Trial Designs
  • Clinical Trial Design: Part 3: Biomarker-Directed Clinical Trials
  • Clinical Trial Design: Part 4
  • Deciphering and Targeting Lysosomes in Cancer
  • Designing Biomarker Studies to Achieve Desired Clinical Applications
  • Methods for Utilizing the Microbiome in Cancer Epidemiology Research
  • Methods to Study Metabolism for Cancer Research
  • Modeling Tumor Dormancy
  • Novel Imaging Strategies in the Metastatic Niche
  • Sample Size and Power Workshop for Basic, Translational, and Clinical Studies

Plenary Sessions
PL01: Opening Plenary: Achieving Equitable Patient Care through Precision and Convergent Cancer Science
Physicist vs. physician: Digitizing clinical assessment, and using it for evidence-based prediction of outcomes
Peter Kuhn, Jorge J. Nieva
Physicist vs. physician: Digitizing clinical assessment, and using it for evidence-based prediction of outcomes
Jorge J. Nieva, Peter Kuhn
Therapeutic implications of DNA repair defects in cancer
Alan Ashworth
Defining the actionable genome
David B. Solit
Precision oncology: The path forward
Levi A. Garraway
Next-generation CAR T cells designed to overcome tumor resistance
Crystal L. Mackall
Role of immune profiling and T cell exhaustion in the response to immunotherapy in cancer
E. John Wherry
PL02: Clinical and Translational Research in Diverse Populations
Title TBA
Olusegun I. Alatise
Spliceomics: Alternative RNA splicing as a source of ancestry-related molecular targets in precision oncology and cancer disparities
Steven R. Patierno
The DARC side of breast cancer disparities: Links to African ancestry and immunologic tumor responses
Melissa B. Davis
Genomic and epigenomic studies of cholangiocarcinoma in diverse populations
Bin Tean Teh
PL03: Manipulating the Immune System in Cancer Therapy
T-cell therapy targeting unique cancer mutations
Steven A. Rosenberg
Redirecting T-cells for cancer immunotherapy using next generation bispecific antibodies and fusion proteins
Pablo Umana
Taming the beast: Strategies to target the immune suppressive macrophage to enhance cancer immune therapy
Judith A. Varner
Mismatch repair deficiency: A connection between the immune system and cancer genetics
Dung T. Le
PL04: Pathogen-Related Cancers: Implications for Populations and Public Health
Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights
Yuk Ming Dennis Lo
Hepatitis B and C virus-related hepatocellular carcinoma in the era of highly active antiviral therapies
Jean-Michel Pawlotsky
HIV malignancies: From despair to gene therapy
Ariela Noy
Therapeutic vaccination to treat HPV disease: Lessons learned from high grade intraepithelial lesions
Cornelia L. Trimble
PL05: AACR Annual Meeting 2019 Highlights: Vision for the Future
Prevention, Early Detection, and Interception
Marcia R. Cruz-Correa
Basic Cancer Science and Translational Research
John D. Carpten
Clinical Research and Clinical Trials and Therapeutics
Patricia M. LoRusso
Wrap-up and Vision for the Future
Elaine R. Mardis

NextGen Stars
The NextGen Stars program provides an opportunity to increase the visibility of early-career scientists at the AACR Annual Meeting, and to support the professional development and advancement of those selected as AACR NextGen Stars. This year, sixteen NextGen Stars will present their work in major sessions.
Wendy Béguelin, Ph.D.
Laura W. Bowers, Ph.D.
Nina J. Chu, Ph.D.
Cosimo Commisso, Ph.D.
Greg M. Delgoffe, Ph.D.
Ann-Kathrin Eisfeld, M.D.
Andreana N. Holowatyj, Ph.D.
Benjamin Izar, MD, Ph.D.
Michalina Janiszewska, Ph.D.
Ashish A. Kulkarni, Ph.D.
Yiting Lim, Ph.D.
David Liu, M.D.
Faruk Mohammed
Tamara Ouspenskaia, Ph.D.
Ferdinandos Skoulidis, M.D., Ph.D.
Liuqing Yang, Ph.D.

AACR 2019 Cancer and Biomedical Research Career Fair
The AACR writes that “whether you are a research scientist or an employer, this is the Career Fair for you, and we invite you to join us for this premier recruiting event.” The career fair is being held Saturday, March 30, 2019, from 9:00 a.m. to 3:00 p.m. in the Georgia World Congress Center. In 2018, more than 3,900 job seekers attended the career fair. Scientists seeking opportunities within academia, government or industry can meet with representatives who are seeking to fill many positions. Job seekers will be able to meet employers face-to-face from academic cancer institutions, the pharmaceutical industry and many other scientifically related organizations; upload CVs/Resumes on CancerCareers.org; and sign up for job alerts.

Career and Advancement
Professional and Career Advancement Sessions
Professional and Career Advancement Sessions are organized to provide important skills to investigators at all levels, from high school students to senior faculty. Programs for high school students and undergraduates require registration. All other Professional Advancement Sessions are available to Annual Meeting registrants free of charge, but attendance is limited to AACR members.
Professional Advancement Session Webcasts
As an additional member benefit, webcasts of selected Professional Advancement Session presentations are now available free to AACR members. Members who have already created a webcast portal account can log in and view these sessions. Members who do not have a webcast account can create an account to begin viewing the career development webcasts.
The following 2018 Professional Advancement Session presentations are available to members as free webcasts:
  • The Critical Role of Physician-scientists in Advancing Cancer Science
  • Challenges and Solutions for Wonder Women in Science
  • Getting Hired!
  • Women in Cancer Research Career Mentoring Session
  • Logistics of Starting a Laboratory
AACRcentral: Networking, Resource, and Career Centers
At the crossroads of the Exhibit Hall, AACRcentral is your one-stop source for information on and assistance with all AACR programs, whether you need to ask a question, find a job, check your email, or meet up with a colleague.
MICR Networking and Resource Center
The Minorities in Cancer Research (MICR) Networking and Resource Center hosts exciting meet-and-greet opportunities with prominent investigators and provides meeting attendees with a comfortable and social environment for networking one-on-one and in small groups. All MICR members and Annual Meeting registrants are encouraged to visit the MICR Networking and Resource Center to learn about AACR and MICR programs, awards, funding and more.
WICR Networking and Resource Center
The Women in Cancer Research (WICR) Networking and Resource Center is the location for networking with members of the WICR Council, WICR Scholars and members of WICR. All Annual Meeting attendees and WICR members are invited to use the Center during exhibit hours for networking, and to learn more about professional advancement opportunities and other programs of interest.
Associate Member Resource and Career Center (AMRC)
The Associate Member Resource and Career Center, organized by the Associate Member Council (AMC), is open to all graduate students, medical students and residents, and clinical and postdoctoral fellows, regardless of membership status. The Center provides an informal place for early-career scientists to connect with colleagues, plan their time at the meeting and learn about programs and other professional advancement opportunities. The AMC Meet and Greet is also held in this location.
AACR Amphitheater
The AACR Amphitheater hosts a variety of sessions, including the AMC-organized sessions for early-career scientists, “Meet the AACR CEO,” and “Meet the AACR President.” All sessions provide a special opportunity for interactive discussion in a small group setting to discuss career paths and vision for the future of the field. All sessions are free; seating is available on a first-come, first-served basis.
AACR Membership Center
The AACR Membership Center provides a place where members can obtain information regarding their membership, join Association groups within the AACR, update contact information, pay annual dues, transfer categories of membership and become familiar with new membership services. Nonmembers are encouraged to visit the Membership Center to submit an application for membership. The AACR is also eager to support the exchange of knowledge and research with investigators who are located in countries with emerging economies. (Significantly reduced membership dues are available for these investigators.)

AACR Scientific Achievement Awards
Since 1961, the AACR has presented hundreds of Scientific Achievement Awards and Lectureships to recognize the scientific accomplishments of basic and translational scientists, physician-scientists, prevention researchers, epidemiologists and other researchers who have made significant contributions to the understanding of cancer biology, diagnosis, prevention and treatment.
A currently announced award winner is Dr. Alberto Mantovani, who will be receiving the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research.

2019 AACR Runners for Research 5K Run/Walk
Whether you’re a walker or a runner, you can team up with the AACR to advance lifesaving cancer research. Members of the AACR Runners for Research team participate in races around the country to support the AACR and the more than 40,000 members who lead the effort to prevent and cure cancer. This year the signature 5K will be held in Atlanta on March 30, 2019, and will start and finish at Centennial Olympic Park. Join the fun to support an important cause at the AACR Runners for Research 5K Run/Walk, and compete for top fundraising and team prizes!

Exhibit Hall Hours
​Sunday, March 31
​1 p.m. to 5 p.m.
​Monday, April 1
​9 a.m. to 5 p.m.
​Tuesday, April 2
​9 a.m. to 5 p.m.
​Wednesday, April 3
​9 a.m. to 12 p.m.

AACR Meetings
Future Annual Meetings
April 25 - 29, 2020
San Diego, California
April 10 - 14, 2021
Washington, D.C.
April 9 - 13, 2022
New Orleans, Louisiana
Other Upcoming Meetings
NIH-AACR Cancer, Autoimmunity, and Immunology Conference
April 15 - 16, 2019
AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research
​April 29 - 30, 2019
AACR International Conference New Horizons in Cancer Research
May 3 - 5, 2019
The Hippo Pathway: Signaling, Cancer, and Beyond
​May 8 - 11, 2019
Accelerating Anticancer Agent Development and Validation Workshop
May 8 - 10, 2019
Bladder Cancer: Transforming the Field
May 18 - 21, 2019

AACR News: Two types of cervical cancer-linked HPV have declined in cervical precancers since advent of HPV vaccine
PHILADELPHIA —An analysis of cervical precancers over a period of seven years showed that two strains of human papillomavirus (HPV) that have been targeted by vaccination since 2006 have declined, accounting for a smaller proportion of cervical disease, according to results published in Cancer Epidemiology, Biomarkers & Prevention.
The study offers evidence that Human Papillomavirus (HPV) vaccination has reduced the incidence of infections that can lead to cervical cancer, said the study’s lead author, Dr. Nancy McClung, epidemic intelligence service officer at the Centers for Disease Control and Prevention (CDC) in Atlanta.
“Almost all sexually active individuals will get HPV at some point in their lifetime, but most HPV infections go away on their own without any treatment,” McClung explained. “If an HPV infection does not go away, it can cause cell changes that, over time, develop into a lesion on the cervix called a cervical precancer. Cervical precancers allow us to observe the impact of HPV vaccination earlier than cervical cancer, which can take decades to develop.”
Previous research has suggested that the incidence of cervical precancer has been decreasing. In this study, researchers sought to determine whether HPV types 16 and 18, which are responsible for approximately 70 percent of cervical cancers worldwide, are also decreasing. These two types have been targeted by the quadrivalent HPV vaccine, which was most typically administered in the United States between 2006 and 2015, and by the 9-valent vaccine that is the only vaccine currently administered in the United States.
As part of the CDC’s HPV Vaccine Impact Monitoring Project (HPV-IMPACT), McClung and colleagues analyzed more than 10,000 archived specimens collected between 2008 and 2014 from women aged 18-39 who had been diagnosed with grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ (CIN2+). Both are precancerous conditions that can arise from persistent HPV infection, and can lead to cervical cancer.
The researchers tested the samples for 37 HPV types, then analyzed the proportion and estimated number of cases by HPV types over time. The researchers found that the number of cases of CIN2+ reported to HPV-IMPACT declined 21 percent, from 2,344 in 2008 to 1,857 in 2014. The estimated number of cases attributed to HPV16/18 declined from 1,235 in 2008 to 819 cases in 2014.
Among women who were vaccinated, the proportion of CIN2+ cases that were HPV 16/18-positive declined from 55.2 percent to 33.3 percent. Among unvaccinated women, the proportion of CIN2+ cases that were HPV 16/18-positive declined from 51.0 percent to 47.3 percent, and among those with unknown vaccination status, from 53.7 percent to 45.8 percent. McClung explained that some vaccinated women were most likely HPV 16/18-positive because they were infected with these HPV types before they were vaccinated. The majority of vaccinated women in this study received the vaccine in their early 20s, after the age most women initiate sexual activity. According to McClung, the decline in unvaccinated women may be due to herd protection.
Researchers noted that every age group saw significant declines in the proportion of CIN2+ cases that were HPV 16/18-positive, with the exception of the oldest group, those aged 35-39. McClung said this finding reflects the fact that most of these women were not eligible for vaccination because of their age. McClung said a limitation of the study was the inability to confirm vaccination status on about 50 percent of the women in the study.
While white and black women saw declines in the proportion of HPV 16/18-positive precancers, Hispanic and Asian women did not. McClung noted that the Hispanic and Asian women included in this study may have been less likely to be vaccinated. But as of 2016, HPV vaccine uptake was robust in Hispanic and Asian teens; therefore, racial and ethnic disparities are expected to diminish, McClung said.
The CDC’s most recent statistics show that 49.5 percent of girls and 37.5 percent of boys aged 13-17 are up to date on all recommended doses of the HPV vaccine. McClung said clinicians should continue to strongly recommend the HPV vaccine for all preteens at age 11 or 12, and effectively answer parents’ common questions about the vaccine. She mentioned that the study indicated that efforts to encourage families to get the HPV vaccination for their teens are paying off, and should be continued.
“This is clear evidence that the HPV vaccine is working to prevent cervical disease in young women in the United States,” McClung concluded. “In the coming years, we should see even greater impact as more women are vaccinated during early adolescence and before exposure to HPV.”

AACR News: Gastric acid suppressants may negatively impact survival outcomes in sarcoma patients treated with pazopanib
PHILADELPHIA — In patients with soft tissue sarcoma, the concomitant use of gastric acid suppressant (GAS) therapy and the anticancer therapeutic pazopanib (Votrient) was associated with significantly reduced progression-free survival and overall survival, according to results published in Clinical Cancer Research.
“Our results indicate that gastric acid suppressants reduce the efficacy of pazopanib in patients with advanced soft tissue sarcoma,” explained Dr. Olivier Mir, medical oncologist and clinical pharmacologist at the Gustave Roussy Cancer Institute, University of Paris-Sud. “Oncologists and pharmacists should pay close attention to patients’ concurrent medications, as they may have a significant impact on cancer treatment outcomes.”
It’s estimated that up to 50 percent of those undergoing cancer treatment utilize GAS therapy. Common GAS drugs include proton pump inhibitors, such as omeprazole (Prilosec) and esomeprazole magnesium (Nexium), or histamine H2-receptor blockers, such as ranitidine (Zantac). In many Western countries, these medications are available over the counter.
Mir noted that the absorption of pazopanib, a multi-kinase inhibitor used in the treatment of renal cell carcinoma and soft tissue sarcoma, is pH-dependent. “We know that pazopanib tablets taken orally need to go into an acidic environment ... in order to dissolve,” he explained. “As the primary function of GAS therapy is to reduce the acidity in the stomach, these drugs can reduce the absorption of pazopanib,” Mir continued.
Previous work has shown that GAS therapy reduced the absorption of pazopanib as measured in plasma in patients with solid tumors. “We wanted to determine if the use of GAS drugs had an effect on survival outcomes in sarcoma patients taking pazopanib,” Mir said.
Mir and colleagues analyzed data combined from two completed clinical trials; one Phase 2 trial evaluated the tolerability and antitumor activity of pazopanib in patients with advanced soft tissue sarcoma, and one Phase 3 trial evaluated the efficacy of pazopanib, versus placebo, in patients with advanced soft tissue sarcoma who received prior therapy. A total of 333 patients treated with pazopanib were eligible for analysis; of these, 117 (35.1 percent) received GAS drugs at least once during pazopanib treatment, 59 (17.7 percent) utilized GAS therapy concomitantly for more than 80 percent of pazopanib treatment duration and 19 (5.7 percent) were already using GAS drugs at the time of trial registration.
Following multivariable analysis, compared to patients who did not use GAS therapy during pazopanib treatment, those who concomitantly utilized GAS for at least 80 percent of treatment duration had significantly reduced progression-free survival (median of 4.6 months compared to 2.8 months, respectively). Concomitant use of GAS also significantly reduced overall survival; those who utilized GAS therapy for at least 80 percent of treatment duration had shorter median overall survival (8 months) compared to those who did not use GAS therapy (12.6 months).
Among the 110 placebo-treated patients from the Phase 3 trial who were eligible for analysis, there were no associations between concomitant GAS use and progression-free survival or overall survival. “This suggests that the drug-drug interaction between GAS and pazopanib directly affected the survival outcomes of sarcoma patients,” Mir noted.
Mir and colleagues also found that GAS therapy did not reduce the frequency of pazopanib-related toxicities.
“I think that our results are practice-changing, and I would discourage oncologists against prescribing gastric acid suppressants when patients are treated with pazopanib, unless it is the only option for the patient. Patients often utilize GAS therapy for abdominal pain, which is not always related to stomach acidity,” Mir concluded. “I would predict that the majority of patients taking GAS drugs could utilize a different therapy to aid in their abdominal discomfort. Moreover, it is important for patients to inform their oncologists of all the medications that they are taking during cancer treatment (including those available OTC) so that potential drug-drug interactions can be identified and avoided.”

AACR News: Patients with BRAF-mutant melanoma genotypes may respond to targeted and immunologic therapies
PHILADELPHIA — Unlike patients with melanoma bearing BRAF V600E mutations, those whose tumors have V600K mutations may benefit less from BRAF and MEK inhibitors and more from anti-PD-1 immunotherapy, according to results published in Clinical Cancer Research.
“The clinicopathic differences previously observed in V600E and V600K BRAF-mutant melanoma can now be explained by their biology. These genotypes should be considered as distinct clinical entities with differing responses to treatments, and they should be managed differently,” said Dr. Alexander Menzies, medical oncologist and associate professor at Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals.
About 40 percent of patients with melanoma bear mutations in the gene BRAF, of which about 70-80 percent are V600E and 20-30 percent are V600K. Patients with BRAF mutations are often treated with targeted therapy, such as BRAF and MEK inhibitors, or anti-PD-1 immunotherapy, Menzies noted.
The researchers have previously published a study that evaluated the clinicopathic features of patients with BRAF-mutant melanoma. “We wanted to explore the molecular basis for differing clinical phenotypes observed between BRAF V600E and V600K melanomas, whether they have distinct response profiles to targeted treatments and immunotherapy, and the biological rationale for different clinical outcomes,” Menzies added.
Menzies and colleagues evaluated baseline samples taken from 93 BRAF-mutant melanoma patients treated with targeted therapy (BRAF inhibitors with or without MEK inhibitors). Of these 93 patients, 73 had V600E BRAF-mutant melanoma, while 15 patients had V600K BRAF-mutant melanoma. Baseline samples were analyzed via gene expression profiling and DNA sequencing, and mutant genotypes were correlated with clinical outcomes.
The researchers also evaluated an independent cohort of 103 BRAF-mutant melanoma patients that were treated with anti-PD-1 immunotherapy (pembrolizumab or nivolumab). Of these 103 patients, 84 had V600E BRAF-mutant melanoma, while 19 patients had V600K BRAF-mutant melanoma. Response to immunotherapy based on BRAF genotype was correlated with clinical outcomes.
In the targeted therapy cohort, compared with patients with V600E mutations, those with V600K mutations had less tumor regression and shorter progression-free survival, although these differences were not statistically significant. In the immunotherapy cohort, patients with V600K mutations had significantly higher progression-free survival compared with patients with V600E mutations (median of 19 and 2.7 months, respectively). While the response rate and overall survival was also higher in patients with V600K mutations compared with patients with V600E mutations, these increases were not statistically significant.
“These findings were likely limited by the small sample size of patients with V600K mutations and relatively short follow-up,” Menzies explained.
Analysis of baseline tumor samples in the targeted therapy cohort showed that patients harboring V600K BRAF mutations had a significantly higher mutational load compared with patients harboring V600E BRAF mutations. Patients harboring V600E mutations had significantly higher expression of ERK pathway genes and significantly lower expression of PI3K-AKT pathway genes compared with patients harboring V600K mutations. Because patients with V600K mutations had increased activation of the PI3K growth and survival pathway, these patients may derive benefit from treatment with PI3K inhibitors.
“Patients with V600E mutations have higher activation of the MAPK/ERK signaling cascade, suggesting that their cancers have greater dependence on this pathway for growth and survival,” explained Menzies. “This explains why patients with V600E mutations have a better response to BRAF/MEK inhibitors compared with patients with V600K mutations.”
The enhanced response to anti-PD-1 immunotherapy in V600K patients can be explained by the increased mutational burden compared with V600E patients, said Menzies, who concluded, “We have shown that V600K BRAF-mutant melanoma patients derive greater benefit from immunotherapy and less from targeted therapy than those with V600E mutations. This suggests that V600K patients should be considered for immunotherapy where possible.”

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