TOPICS: Consulting & Special Projects

Personalized Medicine And Mammograms What Does The Future Hold?

The mammogram debate had some added fuel to fire with respect to the value of screening for breast cancer. This time it was an article from the November issue of the New England Journal of Medicine (NEJM).

The article titled Effect of Three Decades of ScreeningMammography on Breast-Cancer Incidence by Archie Bleyer, M.D., and H. Gilbert Welch, M.D., M.P.H. highlighted that screening mammograms may indeed be resulting in an over-diagnosing of breast cancer.
This was discovered through results of their study including Surveillance, Epidemiology, and End Results data to examine trends from 1976 through 2008 in the incidence of early-stage breast cancer (ductal carcinoma in situ (DCIS) and localized disease) and late-stage breast cancer (regional and distant disease) among women 40 years of age or older.

According to the article, 70,000 patients or 31% of those screened are inappropriately identified in having breast cancer of some significance and thus undergo needless intervention and personal distress. I say “of some significance”, because per a prior presentation by Dr. Welch, these patients do indeed have evidence of cancer that meets the cellular definition but it may be very slow growing cancer, non-progressive, or even regressive; thus the patient will likely die of another cause not breast cancer.

Furthermore, the number of patients who present with late stage breast cancers has not decreased despite the push to get all women over the age of 40 to undergo screening mammography. Finally, it was determined that the reduction in breast cancer-related mortality is not due to more vigorous screening but instead, the availability of more effective treatments.

Needless to say this article, caused quite a stir; enough for it to be covered by the national media. Whereas the reactions ranged from further doubt over the value of mammogram to accusations of “junk science”, it was a comment from Dr. Len Lichtenfeld in an article by CBS News that struck a chord. While Dr. Lichtenfeld, the American Cancer Society’s deputy chief medical officer, chimed in to impart the significant support for screening mammography from high-quality studies, he alluded that the next step is indeed more accurate prognostic indicators. He concurred that over-diagnosis is in fact a problem due to imaging technology which “has brought us to the place where we can find a lot of cancer,” and noted that “science has to bring us to the point where we can define what treatment people really need.”

Enter personalized medicine. As defined by the President’s Council on Advisors on Science and Technology and reiterated by the Personalized Medicine Coalition (PMC)“personalized medicine” denotes “the tailoring of medical treatment to the individual characteristics of each patient…to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.” In other words, treating patients according to their prognosis; which means withholding treatment in cases for which the natural history will yield a good prognosis and when treatment is necessary, providing that which will afford the best response possible.

Can we use technology to determine prognosis and thus avoid unnecessary treatment of breast cancers that are unlikely to progress? Moreover, if treatment is necessary, can technology ensure that the treatment is individualized? To shed some light on this, I have performed a cursory review of technology in the areas of prognostics and treatment targeting. By no means is this an exhaustive analysis – just an example of what is available now specifically for breast cancer or may be in the near future.

Risk Prediction

Myriad Genetics offers a blood test for the BRCA1 and BRCA2 genes (these are tumor suppressor genes located on chromosomes 17 and 13 respectively). When mutated the BRCA1 (BR for breast, CA for cancer) gene is one of the genes responsible for hereditary breast and ovarian cancer. These are known as “tumor suppressor genes”. That is, when non-mutated, the proteins produced by the BRCA1 and BRCA2 genes prevent cells from becoming malignant by assisting in the repair of mutations in other genes through a process known as double-strained DNA repair. Thus, an inherited mutation in either of these genes increases the probability of malignant transformation and cancer. According to Myriad Genetics’ website, approximately 7% of breast cancers are caused by inherited mutations of BRCA1 and BRCA2. This test is targeted to women who have close relatives (1st, 2nd, 3rd degree) who have had breast cancer. Its goal is to determine, through a numerical score, lifelong risk of developing breast cancer in those with a strong family history.

The OncoVue was developed by InterGenetics and unlike, BRCA 1 and BRCA2, is designed for women without a strong family history. Its goal is to identify women at risk of developing sporadic breast cancer rather than hereditary breast cancer. Through a sample of buccal (cheek) cells obtained through oral rinse collection, according to InterGenetics’ website, OncoVue assesses a number of common variations in many genes involved in growth factors, DNA repair, steroid hormone metabolism, DNA repair, free radical scavenger, and cell cycle control. Results estimate a woman’s individual risk by assigning her to a standard, moderate, or high risk groups relative to the average risk for women of their age. It also gives women a score at different stages in her life.

Prognostic Indicators

Agendia’s Symphony is a suite of genomic tests which includes prognostics, targeting treatment, and companion diagnostics for developmental genetic therapies. One component MammaPrint, is designed to determine the intervention strategy for patients with early stage breast cancer (stage 1 or 2) identifying the risk for metastasis. According to Agendia’s website, this test interrogates the critical molecular pathways involved in the breast cancer metastatic cascade and analyzes 70 critical genes that comprise a definitive gene expression signature. Results stratify patients into two distinct groups — low risk or high risk of distant recurrence. A “Low Risk” result means that a patient has a 10% chance that her cancer will recur within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy. A “High Risk” result means that a patient has a 29% chance that her cancer will recur within 10 years without any additional adjuvant treatment, either hormonal therapy or chemotherapy. The test is performed on a tissue sample obtained during lumpectomy.

Probably the technology most relevant to the debate triggered by the NEJM article is the Oncotype DX Breast Cancer Assay for DCIS developed by Genomic Health. DCIS is the earliest form of breast cancer (a.k.a. “stage zero) which forms and is contained in the milk ducts of the breast. It is also the type of breast cancer diagnosis which may be unnecessarily treated. According to Genomic Health’s website, this test is a multi-gene diagnostic assay designed provide an individualized estimate of the 10-year risk of local recurrence (DCIS or invasive carcinoma) to help guide treatment decision making in women with ductal carcinoma in situ treated by local excision, with or without tamoxifen. It analyzes the activity of 21 genes and then calculates a recurrence score number between 0 and 100; the higher the score, the greater the risk of recurrence. As with the MammaPrint, the test is performed on a tissue sample obtained during lumpectomy.

Based on the examples provided, the industry is indeed beginning to move away from the treat-all approach for breast cancers, particularly in very early-stage cancer. Genetic screening tests may help to in fact determine who needs yearly mammograms and when they should initiate. While prognostic indicators do not obviate the need for a lumpectomy in the case of DCIS, they may reduce unnecessary follow-on radiation and therapies such as tamoxifen.

The level of interest we’ve noted in the business, clinical and patient community with regards to risk prediction and prognostic indicators is tremendous. Clearly the debate will continue but the how cancer is diagnosed and treated is changing. From the clinical perspective it will become more acceptable to not treat certain forms cancer based on genetic profile and prognostic indicators. The ability to better predict drug efficacy will also further reshape the market and narrow the focus of many leading oncology drugs. The genetic knowledge will also offer new opportunities for new treatments based on the human genome. The payer community will also have to further adapt to treatment paradigm with more complex and informed treatment pathways. The age of personalized medicine is upon us. Personalized treatment and mammograms is just one example that will be reshaping the life sciences industry over the coming decades.