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 IndicatorsAgendia’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.
Melissa Hammond is Managing Director at Snowfish, a strategic consulting firm specializing in providing unique insight to the life sciences industry.
