Establishing cause and effect is one of the trickiest
aspects of medicine. So-called “causality” can be elusive, especially once you
move beyond connect-the-dots type circumstances (exhibit A; Mom cuts finger
with bagel knife = bleeding Mom.)
Here in Marin, we worry and wonder a lot about breast
cancer. Why does a particular woman get breast cancer? How does another woman
avoid it? These are difficult and often unanswerable questions. Unlike the
knife and finger example, there are a litany of possible reasons why an
individual might develop breast cancer. And, even if we expand the question to what
increases the risk of breast cancer across a broad population, satisfactory
answers are slippery. It is with this in mind that we should view the recent
evidence regarding breast cancer in Marin County.
It is well documented that Marin has historically had an
abnormally high rate of new breast cancer cases. In particular, data from the
late 1990s demonstrate breast cancer rates some 15% higher than those found across
the rest of the state. Multiple culprits – lifestyle, hormones, toxins, and
genetics – have been proposed and studied, without the emergence of a single smoking
gun.
A study recently published in the Journal of the American College of Surgeons has proposed yet
another possible cause – genetic differences in Vitamin D receptors. The study,
conducted by Dalessandri and colleagues, examined the DNA of 164 Caucasian
women living in Marin and diagnosed with breast cancer between 1997-1999. They
compared their genetic profiles with those of 174 breast-cancer-free matched
controls and found that women at statistically high risk for breast cancer were
1.9 times more likely to have a specific difference (called a variant) in the
gene which dictates how the body utilizes Vitamin D (the Vitamin D receptor). Vitamin
D has received quite a bit of attention for its possible benefit in deterring certain
types of cancers and animal models have demonstrated that it has a beneficial
effect on breast cancer tumor growth. Thus, differences in how Vitamin D is
processed by its receptors is a logical explanation for why certain women (in
Marin and elsewhere) would be at higher risk for developing cancer.
But before you march out to determine your Vitamin D receptor
profile, let’s put these findings in proper prospective. First of all, this was
a small “pilot” study and should be considered preliminary evidence. Medical practice
and investigation is ripe with prominent associations that have not borne out
in larger studies; oat bran and heart disease, and (who can forget?) vaccines
and autism, and on and on. In fact, there are more disproven associations in
medicine than proven ones.
A much larger study of Marin Women (the “Marin Women’s
Study” www.marinwomensstudy.org) with 14,000 participants is ongoing and
analysis of their DNA samples (there are some 8500 available) should provide
more robust data on Vitamin D receptor variants and genetic risk. Furthermore,
the genetic data from Dalessandri’s study is from fifteen years ago – during a
time when breast cancer rates were peaking – especially in Marin. While multi-factorial,
we know that this peak was due, in part, to combined post-menopausal hormone (estrogen
and progesterone) therapy – a known risk factor for developing breast cancer,
and a treatment more common (at the time) in Marin than elsewhere in California.
Thus, we must be careful to extrapolate the findings regarding breast cancer
risk from a prior generation to today’s milieu. Finally, one must always be
particularly fastidious when reviewing the results of studies that focus on a
specific proprietary drug (remember Vioxx?) or test. While this study was
funded by state, county and charitable sources, the results quite prominently
affect the fortunes of genetic testing company InterGenetics Incorporated,
which is marketing OncoVue® - a “genetic-base, breast cancer risk test.” Thus, while interactions between genes
and the environment is certainly a promising field, the jury on Vitamin-D
receptors and breast cancer is most definitely still out.
Where then, does this leave us with breast cancer causality?
Well remember, this is tricky – proving a clear-cut link between a dietary
item, personal habit, or medical treatment and a disease process is fraught
with the potential for mis-interpretation. Nonetheless, there are certainly
some risk factors that we can confidently delineate. Some genetic risk is clearly
proven – and a family history of breast cancer is a known red flag – especially
if due to a known BRCA mutation. In terms of risky environmental exposures, an Institute of Medicine committee report
released last year summarizes these quiet nicely as “hormone therapy that
combines estrogen and progestin, exposure to ionizing radiation…excess weight
among post-menopausal women and alcohol consumption.” Other environmental
agents – chemicals such as bisphenol A (BPA) – have been implicated and are
biologically plausible but at this time unproven. Mary Mockus, a surgeon at
Kaiser-Permanente San Rafael and a member of the collaborative Marin Women’s
Study team, thinks that the ‘toxic soup’ present in higher socioeconomic areas
like Marin County is likely to play some role in the higher breast cancer rates,
but that we are unlikely to ever identify one clear cut perpetrator. And, this
then, fits quite well with what we know about causality in medicine.
Thus for Marin women, the best advice for preventing breast
cancer is probably the best advice for preventing many
diseases; sleep well, get regular exercise, know your family’s medical history and
discuss individualized screening plans with your doctor…don’t smoke, avoid
excesses of alcohol, drugs and ionizing radiation, and eat plenty of green
leafy vegetables. And a healthy Vitamin D level (ask your doctor!) won’t hurt
either.
