Profiles in GU Oncology: Heather H. Cheng, MD, PhD

HEATHER H. CHENG, MD, PHD is an Associate Professor in the Department of Medicine, Division of Medical Oncology, University of Washington (UW); Associate Professor, Clinical Research Division, Fred Hutch Cancer Research Center (FHCRC); and Director, Prostate Cancer Genetics Clinic, Seattle Cancer Care Alliance (SCCA). She tells how she arrived at this point in her career, and how she directs her research in genetics to guide the care of prostate cancer patients and their family members who may be at risk for the disease.

Dr Cheng describes herself as a “physician-scientist” or “physician/clinician researcher.” “That means that I spend about one third of my time seeing patients, and the remainder doing clinical research that is relevant to patient care,” she explains.

All her research is directed toward prostate cancer genetics for treatment and for familial implications. “It involves finding ways to improve our delivery of cancer genetics to men with prostate cancer as it relates to their care, their immediate treatment implications, their families, how to design and conduct clinical trials for them and then magnify the benefits for the next generation, meaning their relatives, who are at risk for, but do not yet have prostate cancer.”

Dr Cheng also acts as an Associate Director of the University of Washington Fred Hutch Medical Scientist Training Program (MSTP), which is funded though the National Institutes of Health (NIH). The mission of the UW MSTP is to empower students with clinical and scientific tools to serve their local, national, and international communities. “It’s also a part of my academic work to mentor the next generation of physician-scientists,” Dr Cheng explains. “So the teaching, research, participation in large scale studies, and applying for grants, things like that, are all part of the academic mission. But in the end, they all come back to the patient, because that’s the inspiration for all of the academic work.”

A Research-Focused Career

Most of Dr Cheng’s life to date has been spent in Seattle, where she grew up, although she was born in Taiwan and her parents immigrated to the U.S. when she was 18 months old. “We did not have medical people in my family, but part of the American dream is to come and get a good education and I went into research and medicine,” she notes.

She obtained her undergraduate degree in molecular biology at Princeton University, after which she applied to medical school. “I had an extensive research training, so the pre-med advisor suggested I consider an MD/PhD program and I ended up applying to the University of Washington because it has a great program. I wasn’t really intending to do that,” she confesses, “but I had such a wonderful time at my interview and meeting people who really are at the interface of research and medicine that I decided to give it a chance.” She entered the UW MSTP in 1998. “It’s a long program, approximately 9 years, but wonderful training,” she says. “I really learned how to practice medicine and how to think critically about research questions.”

Dr Cheng is supportive of combining the different cultures of medicine and research. “On the one hand, you absorb all the medical clinical information, but there isn’t quite enough time to have healthy skepticism about the data. Having done a PhD trains you to think about the limitations of the data and what the pitfalls might be to advance knowledge. We’re not as smart as we think we are, and in order to move the needle, you have to understand the limitations of what you know,” she believes.

She received her PhD under the mentorship of Dr. Julie Overbaugh (for research on the mechanisms of retroviral entry) in 2005 and her MD in 2007. She went on to her internal medicine residency in 2007 to 2008, and fellowship training in hematology and oncology between 2009 and 2013 at UW/FHCRC. She joined the UW faculty in 2014. It was during the time of her fellowship that Dr Cheng became interested in applying her research in biomarkers to prostate cancer.

“Biomarkers help us decide how people might do with respect to their cancer, or what treatments they may benefit from, and for prostate cancer, that hasn’t been as mature as some of the other cancers, like chronic myelogenous leukemia (CML), for example,” she notes.

On a more personal level, Dr Cheng’s interest in prostate cancer is in large part due to the number of men in her family affected by the disease. “It’s the cancer that affects my family the most, so it’s something that I think about a lot,” she admits. During her fellowship time, she saw a 43-year-old patient with metastatic prostate cancer, whose disease “despite all the exciting new treatments available at the time such as abiraterone acetate, enzalutamide, and sipuleucel-T, was not slowed one whit by any of these treatments. It was really sobering. I observed that he had a strong family history of cancer other than prostate cancer and I thought this might play a part in the risk to his family.” At the time, there was a recognition that prostate cancer is genetically related, such that having a family history of cancer, not just prostate cancer, was a risk factor.

Genetic Testing for Prostate Cancer

From 2015 to 2016, there was a “huge shift” in the story of genetics in prostate cancer, when UW/FHCRC investigators working with others made two important discoveries, Dr Cheng recalls.¹ First was that about one quarter of patients with prostate cancer have specific mutations in DNA repaired genes, such as BRCA2, ATM, CHEK2, and others, that make them candidates for platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors.

“At that time, PARP inhibitors were not on the radar of prostate cancer, although they were used in ovarian and breast cancer,” Dr Cheng notes.

The second discovery was that 10% of those men have the mutations running in their families, and the men in their families have a 50% chance of inheriting the same mutation that may increase their risk of prostate cancer. Dr Cheng credits the expertise in cancer genetics at UW at that time, including mentor and friend Mary-Claire King, PhD, Professor of Medical Genetics and Genome Sciences; She also credits Drs. Evan Yu, Bruce Montgomery, Dan Lin and Pete Nelson for mentorship and sponsorship in prostate cancer research, as well as critical support at an important time in my career from the Prostate Cancer Foundation; and Colin C. Pritchard, MD, PhD, Professor and Co-Director, Genetics and Solid Tumors Laboratory, who was developing cancer genetics in prostate cancer.

“I was fortunate in having the opportunity at that moment to help on the clinical implementation side,” Dr Cheng recalls.

In 2016, Dr Cheng launched the Prostate Cancer Genetics Clinic at the UW/SCCA to address translation of these genetic and genomic discoveries to clinical care. The clinic was among the first of its kind and serves as a clinical base for genetic counseling, testing, and matching prostate cancer patients with precision oncology clinical trials and translational research opportunities. It also connects family members with opportunities for early detection and prevention of cancer. “We are still trying to learn about these genes through efforts like the PROMISE registry (Prostate Cancer Registry of Outcomes and Germline Mutations; NCT04995198) and the GENTleMEN study (Genetic Testing for Men with Prostate Cancer); (NCT03503097), Dr Cheng notes.

These studies offer free genetic testing to men with advanced prostate cancer to determine whether they’ve inherited alterations in genes linked to this prostate cancer. Dr Cheng is also involved as PI or coordinator in clinical trials of screening and of new treatments for prostate cancer, including AMPLITUDE (NCT04497844)—a Phase 3 study of abiraterone plus prednisone with or without the PARP inhibitor niraparib for the treatment of men with DNA repair mutations such as BRCA-1, BRCA-2, CHEK2, etc, in the metastatic hormone-sensitive setting.

“Right now, the approval for PARP inhibitors is in the metastatic castration-resistant setting in the second line, and I think with time, these drugs will move to earlier into the disease space,” Dr Cheng predicts. A trial currently going through the National Clinical Trials Network (NCTN) is a study of neoadjuvant platinum for men with high-risk localized prostate cancer with BRCA-1 and BRCA-2. We hope that when people have curative intent surgery they often will receive, in the right clinical context, chemotherapy prior or surgery to help improve the odds of cure.”

A Joint Effort in Raising Awareness

Dr Cheng hopes that male siblings of prostate cancer patients will enroll in trials like the PATROL (Prostate Screening for Men with Inherited Risk of Developing Aggressive Prostate Cancer) study (NCT04472338). “I hope we’re going to have options for targeted precision therapy throughout the disease spectrum from the very beginning to the very end, and by knowing about it early and having men be aware of their risk, just like we do in breast and ovarian cancer, we can change the natural history and improve people’s outcomes as early as possible,” she says.

There is still much more work to do to raise awareness of genetic risk in prostate cancer, Dr Cheng admits. “We have to ensure that everyone has access and that we don’t leave anyone behind. A lot of work must be done to understand the genes we already know, and there are a lot more out there. It is the next frontier of how we can advance and be more precise, but we have a lot of learning to do before we can really deliver on that potential.”

This will require partnership with patients and with their physicians. “We all have to work together to realize the maximum potential,” she says. “That’s the excitement of the field that I have.”

Linda Brookes, MSc is a freelance medical writer/editor based in New York and London.

References

1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. DOI: 10.1056/ NEJMoa1603144
2. Link to PROMISE site: www.prostatecancerpromise.org/?utm_campaign=GU-OncologyNow&utm_medium=link&utm_source=Website&utm_content=Inte