The Promise of Precision Medicine for Breast Cancer
This month marks my 12th “cancer-versary” as they call it. The timing is of particular significance this year, hence this blog. With every mammogram, I hold my breath – hoping for a good result. Now, with some recent advances, there is new hope for the >123,000 diagnosed each year in the USA and >23,000 diagnosed each year in the UK. In the last four weeks alone, there have been not one, not two, not three but four incredible announcements made regarding the advances in breast cancer. Twelve years ago, these treatment concepts were barely nascent. Each is at the forefront of combinatorial therapy and advances science one giant step towards precision medicine.
ONE, Judy Perkins is a lucky lady! She holds the remarkable and unique distinction of being the first terminally-ill, late stage, metastatic breast cancer patient to be cured. Tumor infiltrating lymphocytes (TILs) were harvested from her tumors, propagated, screened, isolated, cultured then re-injected back into her body with a heavy dose of pembrolizumab (1). Nearly one year later, Judy is still cancer-free. Of course, n=1 and it hasn’t worked in other patients yet, but it’s a helluva “one”.
TWO, for some patients, chemotherapy may no longer be a necessary part of treatment (2) given that the side-effects outweigh the benefits. Results from a trial with >10,000 ER+, HER2- breast cancer patients were just presented at ASCO. Previously, it was unclear if patients with mid-range risk of recurrence scores of 11-25 on the Oncotype™ DX test would benefit from adjuvant chemotherapy. The study demonstrated how this 21-gene text can be confidently used to inform treatment plans which no longer need to include chemotherapy for patients who score 0-25.
THREE, some patients with Triple Negative breast cancer may finally have a treatment option. Researchers at the Mayo Clinic recently demonstrated that a drug approved by the FDA for the treatment of myelodysplastic syndrome inhibited the growth of aggressive triple negative tumors and tumors resistant to chemotherapy in a cohort of patients who expressed critical DNA methyl transferase proteins (3). Moreover, the drug can be applied at a relatively low dose which might reduce the toxicity and allow it to be used for a longer time, which could help boost its efficacy.
FOUR, researchers in Montreal at the Clinical Research Institute and the local university’s Faculty of Medicine discovered a protein (AXL) which, when deactivated, prevented the development of metastases in a HER2+ breast cancer (4). AXL protein stimulates cell proliferation and influences survival. The research was conducted in mice but the results will now be used to inform future efforts to develop a treatment that targets AXL.
COMBINATORIAL ANALYTICS MAY BE THE ENABLER TO PRECISION MEDICINE
To date, researchers have been analyzing the effects of one gene, at best two, on a disease state but this is not how complex diseases operate. Plus, scientists are increasingly finding that diseases are spectral with tremendous variation across cohorts, hence the critical need for higher order analysis on datasets that span populations to personal factors. Interdependencies of biological pathways affected by disease are poorly understood but, once better studied via combinatorial analytics, new combinatorial therapies (which have multiple targets across more than one pathway) can be developed. Researchers at UCSF have recently mapped 625 genes associated with breast and/or ovarian cancer to nearly 100 FDA-approved chemotherapy drugs to enable clinical decision support and precision medicine (5). Survival is literally at stake: a study presented last week at ASCO by researchers at MD Anderson revealed that patients were six times more likely to survive 10 years if they received treatment tailored to their unique genetics (6).
To that end, I am encouraged by the in silico discoveries recently made by precisionlife™. These include multiple gene signatures (combinations of variants) that appear to have a protective effect, new drug targets and a novel method for enabling combinatorial therapies. Additionally, some possible new indications for existing drugs (7). That said, of course these in silico discoveries need to be moved to the lab then to the clinic to be validated, but the data provide a good springboard for further research and the promise of precision medicine.
So what’s next? Prospective clinical trials exploring these newly discovered mechanisms of action, drug targets and biomarkers as potential informants for disease are moving forward as the collective, global march down the path of precision medicine continues. CRISPR, as a precise gene-editing tool, may be the greatest discovery since PCR yet research there has only just begun. The dawning of combinatorial analytics is here and promises to elucidate novel patterns across data types revealing associations between disease, risk and potential response to treatment. The potential for discovery and impact is enormous. But, until more research is conducted, many of us will still be holding our breath …
1. Sample, Ian & Glenza, Jessica. “Doctors Hail World First as Woman’s Advanced Breast Cancer is Eradicated.” The Guardian. June 4, 2018 LINK
2. Sparano, Joseph A. et al.. “Adjuvant Chemotherapy Guided by a 21-gene Expression Assay in Breast Cancer.” New England Journal of Medicine. June 3, 2018 LINK
3. Gallagher, Colette. “New Potential Treatment Option for Triple-Negative Cancer.” Science Daily. May 21, 2018 LINK
4. University of Montreal. “Breast Cancer: Discovery of a Protein Linked to Metastasis.” Medical Express. May 7, 2018 LINK
5. Weiler, Nicholas. “Gene Mapping Lays Groundwork for Precision Chemotherapy.” UCSF. Apr 17, 2018 LINK
6. Glenza, Jessica. “Tailoring Cancer Treatment to Genetic Profile Extends Lives, Study Finds.” The Guardian. June 6, 2018 LINK
7. Møller, Gert. “Detection of Clinically Relevant High Order Epistatic Interactions in a BRCA2 Positive Breast Cancer Population.” May 29, 2018 LINK