The Promise of Precision Medicine for Breast Cancer
Guest Blog by Loralyn Mears, PhD
We’ve all seen the pink ribbons. Some of us have even worn them while others have intimate, personal knowledge of the disease. Many have donated to it. Some treat it while others study it. Each of us in these various roles is part of that pink ribbon family, committed to doing whatever we can to change the outcome for all those affected by it. To this end, precision medicine holds enormous promise with the ultimate goal of treating each patient individually by approaching breast cancer disease as an “n” of one.
Over the past decade, breast cancer has consistently held the position of “best-funded cancer”. And the numbers are staggering. Some estimates suggest that global breast cancer fundraising efforts exceed $5-6B annually. An informed statistic on the NCI budget disclosure page (LINK) reveals that, in 2017, the NCI alone spent ~$520M on breast cancer research. To this end, the money appears to have been well spent given the numerous advances in our collective understanding of the disease and how we treat it.
KEY EVENTS in the HISTORY OF BREAST CANCER:
- Breast cancer (aka “ulcerated breast”) believed to be first described in ~1600 BC
- 1932 began the era of breast conservation coupled with radiation by 1937
- 1962 ICI Laboratories (now part of AstraZeneca) developed Compound ICI 46,474 which failed as a contraceptive – scientist Arthur Wapole insisted development continue as a breast cancer therapy
- 1978 the FDA approved Compound ICI 46,474 (aka Tamoxifen) as the first estrogen receptor targeting therapy
- 2001 sales of Tamoxifen peaked at $1.1B/yr and still post revenues >$400M/y (including generics)
- 2016 Sir Mike Stratton of Cambridge Research identified 93 genes associated with breast cancer
- 2016 Professor Guillaume Tcherkez identifies blood-based biomarkers for diagnosis
- 2017 mortality rates are half of what they were 20 years ago yet a woman still dies every 12 min
- 2018 the first terminally-ill, late-stage, metastatic breast cancer patient is cured
- 2018 repurposed drug inhibits aggressive tumors in Triple Negative Breast Cancer patients
- 2018 the 21-gene Oncotype™ DX test shows chemotherapy is not required for scores 0-25
- 2018: 231,000 new breast cancer diagnoses each year with 40,000 deaths in the USA
SURIVIVAL RATES CONTINUE TO IMPROVE HOWEVER …
According to the American Cancer Society, in the USA, there are about three million breast cancer survivors with 231,000 new cases diagnosed each year and 40,000 deaths despite a 25 year history of consistent decline in the mortality rate (LINK). Breast cancer is believed to have been first documented around 1600 BC in Egypt based on the 1860 discovery of the Edwin Smith Papyrus in an Egyptian tomb which described eight cases of an ulcerated breast. Breast Cancer (formally defined as such) has been around for over 250 years and research efforts dedicated to curing breast cancer began in earnest nearly a century ago (LINK). In 1932, Dr. David Patey began a movement towards breast conservation by developing the modified radical mastectomy surgical procedure to reduce disfiguration and scarring. In 1937, Sir Geoffrey Keynes was practicing breast conservation coupled with radiation. By the 1990’s, breast conservation was eventually widely adopted following a large clinical trial by NCI in 1985 which demonstrated that the procedure (also known as lumpectomy) was as effective as radical mastectomy for specific cases.
Tamoxifen, perhaps the best selling drug of all time with respect to breast cancer therapy, had a bumpy start. Arthur Walpole, a scientist working at ICI Laboratories (now part of AstraZeneca) in 1962, developed Compound ICI 46,474 as a contraceptive. However, the compound failed miserably in clinical trials as it stimulated rather than suppressed ovulation and, for various reasons, it could not be patented in the USA – the largest target market (LINK). Walpole insisted development continue on the compound as a breast cancer therapy. Fast forward twenty years when clinical trials demonstrated that Tamoxifen, as it came to be known, was highly useful as an adjuvant to surgery and chemotherapy and prevented recurrence. Hence it was regarded as the first preventive for any cancer. By 2001, Tamoxifen sales were in excess of $1B/yr and still boast a healthy revenue stream of >$400M/yr (including generic versions)(LINK, LINK, LINK).
Throughout the 1990’s and earlier part of the current century, numerous studies revealed the connection between hormonal modulation therapies (such as ERT), the use of contraceptives and the effects of life style (for example, smoking and drinking) and breast cancer (LINK). The practice of neoadjuvant chemotherapy (aka pre-operative), sentinel lymph node removal and biopsy along with Lymphatic System mapping emerged as the standard of care during this period.
RECENT BIG BREAKTHROUGHS
2016 was a break-through year for breast cancer under the leadership of Sir Mike Stratton, employed by Cambridge Research Institute at that time, led his team to discover 93 genes associated with breast cancer, paving the way for future analysis and therapy efforts (LINK). Additional efforts in Europe, such as those by Professor Guillaume Tcherkez, had identified that changes in the proportions of carbon-13 and nitrogen-15 could reveal the presence of breast cancer in the blood. This advancement is now setting the course for blood-based biomarker analysis which could help increase detection of the disease since mammograms, which are the current standard, are inaccurate 16-19% of the time (LINK). Illumina, a pioneer and leader in the field of innovative diagnostics, is currently developing an all-in-one liquid cancer biopsy designed to detect any and all types of cancer: success in this regard could revolutionize diagnosis (LINK).
Compared to 2018, the awe-inspiring breakthroughs of 2016 seem relatively minor. In the past two months alone, there have been multiple advances in breast cancer (some of which were previously inconceivable) with each advance made possible via decades of prior research. Just a mere twelve years ago, at the time of my own diagnosis, these research efforts were barely conceptualized and today, they are already changing lives. Each is at the forefront of combinatorial therapy and advances science one giant step towards precision medicine:
- Judy Perkins may be the luckiest terminally-ill, late-stage, metastatic breast cancer patient in history as she is the first to formally be called “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 (LINK). Nearly one year later, Judy is still cancer-free.
- A new study demonstrated how the 21-gene Oncotype™ DX test can be confidently used to inform treatment plans which no longer need to include chemotherapy for patients who score 0-25 (LINK). Previously, it was unclear if adjuvant chemotherapy afforded patients who scored in the mid-range of 11-25 any benefits.
- The Mayo Clinic found that Triple Negative breast cancer patients who express critical DNA methyl transferase proteins (LINK) show tumor growth inhibition after receiving low doses (hence, reduced toxicity) of a drug originally intended to treat myelodysplastic syndrome.
- When protein AXL is deactivated, metastases were prevented in HER2+ breast cancers in mice (LINK) as shown by researchers at the Montreal Clinical Research Institute. A bold first step towards identifying treatment options for this aggressive and poorly studied type of cancer.
- 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 (LINK).
We need precision medicine to usher in the next series of break-throughs. Survival is literally at stake: a study presented last month 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 (LINK). Of course, it will take a yeoman’s work effort, diligence, brilliance and a spot of luck to cure breast cancer – perhaps eliminating it before it begins – but the results of the last few months alone, not to mention the tremendous advances over the past century, suggest that it *is* possible to do so. But we’re not there yet … there is still much more to learn, discover and do.