Biopsies before, during, after therapy and deep molecular analysis seek tumor tricks to target
A study that indicates how advanced melanoma responds to an immunotherapy, published in Cancer Discovery, demonstrates a revolutionary approach from The University of Texas MD Anderson Moon Shots Program that relies on longitudinal sampling and deep molecular analyses to understand the dynamics of cancer response to treatment.
“Cancers are exceptionally adaptive in the face of treatment pressure,” said Andrew Futreal, Ph.D., interim chair of Genomic Medicine and co-leader of the Moon Shots Program. “We know a tumor after therapy is likely to be different than before, but we haven’t done a good job at tackling this from a research perspective until now.”
Futreal also co-leads the Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO) platform, designed to get a scientific grip on the extreme survival skills of advanced cancers.
APOLLO will gather high-quality biopsies and blood samples taken before, during and at the end of treatment, prepare them for genomic/molecular analysis and immune response monitoring by expert platforms, and then deposit the results, with clinical information, in a secure, comprehensive database for researchers to address crucial questions and improve treatment.
“APOLLO provides standardized collection of high-quality longitudinal samples that will allow us to conduct the deep molecular analysis over time and under therapy that we need to make practice-changing advances for patients,” Futreal said.
The idea is to understand factors that lead to tumor response, non-response or development of resistance to treatment in diseases that are tenacious moving targets for therapy. More effective use of targeted therapies and immunotherapies depends on such knowledge.
In the next two years, APOLLO is scheduled to conduct such analyses in 2,100 patients enrolled in 28 high-priority clinical trials for melanoma, multiple myeloma, glioblastoma, lymphoma, lung, breast, colorectal, pancreas, ovarian cancers, sarcoma, and cancers caused by the human papilloma virus.
In the study reported in Cancer Discovery, gene expression and immune biomarkers analyzed in pretreatment biopsies did not predict response, but early on-treatment biopsies uncovered important immune biomarkers of response.
“Certainly, finding predictive biomarkers in pretreatment biopsies is the Holy Grail, but pretreatment and early on-treatment biopsies might be a winning combination,” Futreal said.
Beyond that initial biopsy
Research with serial biopsies is important to understand what is happening with the cancer on a molecular level and build a knowledge base leading to the use of repeat biopsies routinely in the clinic.
“If you don’t get a biopsy after treatment, you are not going to learn about tumor evolution and mechanisms of resistance to treatment,” said Ignacio Wistuba, M.D., APOLLO co-leader and chair of Translational Molecular Pathology.
This is a strategy employed by Jennifer Wargo, M.D., associate professor of Genomic Medicine and Surgical Oncology, leader of the melanoma research published in Cancer Discovery, who has been involved in APOLLO development since her recruitment to MD Anderson in 2013.
“We should be incorporating analysis of longitudinal tumor and blood samples into clinical trials, and ultimately we may even incorporate this into treatment with standard of care therapy. This effort is critical to guiding patient care in this era of precision medicine” Wargo said.
Cancer patients generally undergo an initial biopsy, with progression measured after that by CT or MRI scans for size and volume and PET scans for metabolic activity.
Futreal compares current biopsy practice to imaging. “We don’t take one CT scan initially and then use that same scan to assess how well treatment is working three months later. We take a new scan,” Futreal noted.
Biopsies may be taken surgically, or via endoscopy or with radiologically guided core needles or fine needles that extract small samples from less accessible tumors, and potentially from circulating blood.
While taking biopsies after treatment makes scientific sense, there are associated risks and the benefit of doing so hasn’t been proven, which means insurers and other payers don’t cover the cost.
“We have to build the evidence first, you can’t just go full bore into clinical implementation of this until we generate and analyze the data in the research setting,” Futreal said.
Patients enrolled in clinical trials under the APOLLO protocol are asked to consent to repeat biopsies and multiple blood draws. They may also refuse to have biopsies at any time during the study.
The development of liquid biopsies – blood tests that allow less-invasive analysis of tumors before and after treatment – will be a perfect fit for this approach, Futreal noted.
Big data: the Translational Research Accelerator
Under the APOLLO protocol, biopsies are taken to the institutional tissue bank for processing and distribution. A new Research Biospecimen Qualification Lab, directed by Dipen Maru, M.D, professor of Pathology, will also assess the quality of biopsies and provide feedback.
Samples will then go to the:
- Moon Shots Cancer Genomics Laboratory platform for deep DNA and RNA sequencing and epigenetic profiling.
- Immunotherapy platform to gauge the status and density of immune cells in the tumor and its microenvironment as well as the expression of proteins that stimulate or shut down immune response.
- Translational Molecular Pathology, for liquid biopsy profiling, including circulating tumor cells, circulating cell-free DNA and sequencing of DNA and RNA found in exosomes, tiny membrane balls also found in the blood.
Results of these analyses, plus clinical information, will be added to the Translational Research Accelerator, a big data platform that integrates longitudinal clinical and research data in a purpose built infrastructure to support translational research institutionwide.
Information from approximately 250,000 patients treated at MD Anderson since Jan. 1, 2012 has been loaded into the secure database. Research data from Moon Shots Platforms is being added, with full introduction and availability of the platform set for the fall.
Ultimately, with APOLLO providing a regular pipeline of comprehensive data, the goal of the project is for all MD Anderson patients to contribute to and benefit from research.
Source – MD Anderson Cancer Center