Faulty BRCA1, BRCA2 genes: how poor is the prognosis?

Abstract

We take a critical look at the meaning behind the number 87% given to 25-year-old Sophie, a BRCA1 and BRCA2 carrier. Sophie has been told she has an 87% chance of getting breast cancer. She is contemplating a preventive double mastectomy after genetic counseling and her physician's advice. Some 92% of British general practitioners are in favor of prophylactic mastectomy as a treatment option for women similar to Sophie. The treatment decision results, to a very large extent, from the size of the number (87%) alone. The central argument of this study is that physicians, their patients, and the public need a much better understanding on what is meant by probability estimates of 0.87. The figure on its own does not tell us much, and we need to be very cautious in its interpretation. It is important to know that the very same genetic and statistical models, and observed data, resulting in a verdict of an 87% lifetime chance of getting breast cancer, based on BRCA1, BRCA2, and familial information, simultaneously show Sophie to have a greater than 99% chance of surviving beyond the next 5 years cancer free. If she succeeds—the chances are overwhelmingly in her favor—then, given that fact, her chances of surviving a further 5 years are once again greater than 98%. Her chances of not dying due to breast cancer over the next 20 years are greater than 97%, a percentage that changes little if instead of 20 we write the number 30. In a word, although the diagnosis of a faulty BRAC gene may be a disappointment, there is no immediate peril and no need for undue alarm. Sophie, and her primary care providers, can carefully consider her options without feeling that they are under any kind of acute pressure. Whatever the threat, it is not an imminent one.

Introduction

Cancer centers throughout the United States, and, almost certainly, a number of other countries have recently registered a significant increase in demand by women to be tested for the presence of one or two of the genes associated with breast cancer, BRCA1 and BRCA2. The publicity surrounding the elective preventive mastectomy of the well-known actress, Angelina Jolie, will at least in part have contributed to this phenomenon. Other recent highly visible cases—former X Factor judge, Sharon Osbourne, that of Allyn Rose, Miss Maryland, USA, Miss District of Columbia, and a Miss America contestant—have put the spotlight on the question of prophylactic surgery for carriers. In this study, we consider the case of Sophie, a 25-year-old carrier of BRCA1 and BRCA2, who has been advised to undergo a prophylactic mastectomy. According to the U.K.'s National Health Service, a woman with a faulty gene has a 0.5 to 0.85 probability of developing breast cancer. This figure prompted Ms. Osbourne to say that choosing the surgery was a “no-brainer.” One supporter, 38-year-old Emma Parlons who underwent the procedure 3 years ago, made the observation “if somebody said your flight was 87% likely to come down, you wouldn't get on that plane.” Dr. Manny Alvarez, senior medical consultant for Fox News, summarizes Ms. Jolie's decision as “a courageous one, but also likely the right one.” Some 92% of British general practitioners are in favour of prophylactic mastectomy as a treatment option for women similar to Sophie [1]. There appears to be a strong consensus. However …

After a test for the presence of BRCA1 and BRCA2, any woman—in most cases perfectly healthy up to this point—will need to make a decision about what to do next. This decision will be made, for the most part, on the basis of a number given to her. The number lies between 0 and 1 and, in the case of Sophie, was equal to 0.87. As usual, the woman (at this point, we might refer to her already as a patient) and her physician will be involved in any such decision. In addition, at least one other party will be involved in the initial discussions, her genetic counselor. Depending on the outcome of discussions between these three, then others, such as clinical oncologists, surgeons in particular, as well as cosmetic reconstruction surgeons, will become part of a team providing care for Sophie.

What is unusual—unprecedented in the history of medicine until very recent times—is that “treatment” decisions for someone otherwise perfectly healthy are being based on a simple number not measuring any clinical or physiological characteristic, a number described as a probability when on the scale (0,1) and, otherwise, as a percentage when rescaled by multiplying by 100. Other factors of course will have led, in several cases, the woman to consult in the first place, for example, a belief that the incidence rate of breast, or other, cancers among relatives is higher than that might be expected under an assumption of a random distribution throughout the population. This is not an easy concept to understand and we return to it below. But, whatever the woman's initial perceptions leading her to consult, her ultimate decision, mindful of the advice given by her physician and genetic counselor, will be guided by the number lying between zero and one. All three people await the calculation of this number by genetic experts, and genetic epidemiologists and, finally, when the verdict is in, this number—let's call it θ where $0<\theta <1$—will be the overwhelming deciding factor on what to do next. If θ is close to 1, as it is for Sophie, then the sentiment is that some kind of preventive action is required.