Studying the Genetics of Breast Cancer

Genetics has played an ever-increasing role in advancing the understanding and treatment of various cancers in recent years, and of all the cancers, breast cancer has arguably demonstrated the most measurable progress from the application of genetics.

Major strides around identifying genetic risk factors of breast cancer have helped to differentiate between high-risk and low-risk populations and tailor the appropriate detection and preventative measures accordingly.

The biggest recent finding related to genetic risk factors is the recognition of an inverse relationship between the frequency and the potency of genetic risk factors – the more frequent genetic risk factors usually happen to be the least potent. For example, a polymorphism sequence variation in a gene called FGFR2, a fibroblast growth factor receptor 2, is a very weak risk factor but a very common gene.

At the other end of the spectrum is a gene called p53, which is responsible for a syndrome called the Li-Fraumeni syndrome. According to Iglehart, virtually 100% of people who carry a mutation in p53 in their germ line will get cancer, though the frequency of mutations in the p53 gene is extremely small.

One of the most significant and widely discussed findings in the field of breast cancer in recent years has been the identification of genes BRCA 1 and BRCA 2, and the high-risk associated with individuals who have mutations in either gene for developing breast or ovarian cancer.

Due to both high frequency and high potency, BRCA1 and BRCA2 are of greatest concern among genetic risk factors in the clinical setting today, and the gene mutations are severe enough to have a measurable impact on the US population. In addition, certain populations – such as Eastern European Jewish, French Canadians, Welsh, Icelandic or Finnish – display higher incidences than other parts of population in that they seem to be fairly common genetic abnormalities. Roughly 50-70% of patients with mutations in either one of these genes will develop breast cancer at some point in their lifetime.

Of course, other genes fall in between the extremes of the relatively uncommon with high potency – and the highly common but low potency – risk factors. Two such genes, BACH1 and PALB2, offer a relatively strong increased risk of developing breast cancer – a fivefold or sixfold increase in risk from the general population’s risk – and impact approximately one percent of the population. However, the level of risk is fairly low and is comparable to atypical hyperplasia found on a breast biopsy.

While many risk factors have been identified with varying degrees of frequency and potency, still more need to be discovered. “What we really need is a risk factor for estrogen receptor-negative breast cancer, which is a high-grade, hard-to-treat, and all too frequently, lethal disease,” Iglehart says. “If we had a really good risk factor of some sort of estrogen receptor-negative breast cancer, that could be useful. People are continuing to look for risk-associated genes, but there is always that interplay between how common is the gene mutation or alteration in the population, versus how potent is the alteration or mutation in the gene.” 

Identifying four distinct breast cancers

One of the biggest shifts in the understanding of and approach to breast cancer is no longer viewing breast cancer as one singular disease. “There has been a real sea change in the way in which we think about the disease that people may not be aware of,” Iglehart points out. “It’s the realization that breast cancer is not one disease, but is several diseases – at least four separate and very distinct diseases.”

The growing realization of how distinctive the different types of breast cancer are has been propelled by the use of targeted therapies, which emphasize the efficacy of a certain therapy for a particular subtype. Another aspect that solidified the distinctions among breast cancers is the development of genetic technologies that have allowed the scientific community to comprehensively profile the entire cancer genome.

The first identified cancer is estrogen receptor-positive breast cancer (hormone-sensitive breast cancer). “ER-positive breast cancers make up about 60% of all breast cancers with tumors that tend to be sensitive to endocrine therapy, hormone treatments, tamoxiphin, aromatase inhibitors, and so forth,” Dr. Iglehart says.

Within ER-positive breast cancer, the diseases are divided among high-grade and low-grade – with the high-grade version being an aggressive, high-grade, rapidly proliferative, frequently metastatic disease that is not very responsive to hormone therapy. Patients with low-grade, ER-positive breast cancer have a greater chance of being cured since it is slower to develop and not a very metastatic disease.

While both are ER-positive, the divide in grades makes them two very different diseases. Though there do exist intermediate grades of the disease, the tumors typically sort themselves into high-grade or low-grade diseases and there aren’t very well developed methods for making the distinction. Today medical oncologists often use a test called Oncotype DX from Genomic Health to distinguish high-grade ER-positive from low-grade ER-positive.

The third type of breast cancer, HER2-positive, is responsive to HER2 directed therapy and has made headlines recently thanks to the antibody Herceptin and its proven reduction of patient recurrence odds recognized by the medical community. “Herceptin is a big deal because it was shown that the addition of Herceptin to chemotherapy for patients with HER2-positive disease could reduce by about half the number of recurrences when given as an adjunct to surgery,” Iglehart says.

Accounting for approximately 20% of all breast cancer, immunohistochemical tests for HER2 are now routine and a 3-plus positive by immunohistochemistry leads to the diagnosis of HER2-positive breast cancer. The 3-plus positive result originates from an actual genetic lesion that’s an amplification of the HER2 and chromosome 17, which drives high-level over-expression.

The last distinct type of breast cancer is the triple negative breast cancers – ER, PR and HER2-negative. According to Iglehart, these were once considered a ‘wastebasket’ diagnosis, but have since been recognized to be a very homogenous and distinct group of tumors unlike the rest of breast cancers. The triple negative breast cancers account for approximately 15% of breast cancers. First recognized by gene expression arrays, later findings showed that patients with a BRCA1 mutation get triple-negative breast cancer approximately 85% of the time.

Progress in clinical trials

Another sea change in the arena of breast cancer is the approach to clinical trials. Clinical research was once based on large, randomized controlled clinical trials with hundreds of participants that could take years upon years before completion only to yield an average as the final outcome.

While the trials would have potential to cure a good percentage, there wasn’t an ability to identify which participants benefited and why – bringing to light the need to subtype the disease to identify if Type 1 individuals respond to Drug A versus Drug B, etc. Medical professionals have found the answer to be to treat individuals preoperatively, and in the context of breast cancer, to administer therapy when the tumor is still in the breast, in order to see whether the tumor is or isn’t responding to therapy.

“There’s been a shift in thinking that the best way – or at least another way – to do clinical research is to do preoperative clinical trials,” Iglehart says. “If you do preoperative therapies in each of the subtypes of breast cancer, using what you think are going to be the most effective drugs for that subtype, you’ll find out very quickly whether you’re right or wrong because you’ll see whether the tumor responds or doesn’t respond to the treatment.”

The paradigm shift goes hand in hand with the realization that breast cancer consists of multiple diseases, and therefore, preoperative therapy is advantageous along with the practice of dividing clinical trials into subgroups. This type of preoperative approach to clinical trials has already been implemented in most of the major medical centers for breast cancer across the country, including Memorial Sloan-Kettering, Dana-Farber, and others.

Using preoperative clinical trials with fairly well defined subgroups is beneficial for identifying the exact kind of treatment needed for the specific cancers. “For a patient who does preoperative therapy, there’s a possibility that she can achieve breast conversion – that the tumor will shrink to the point where individual might have a lumpectomy rather than mastectomy,” Iglehart says. “So the benefit for the patient is not only the knowledge of whether the therapy works, but also the potential to have a lumpectomy where she otherwise would have to have a mastectomy.”

Less surgery naturally minimizes the possible adverse effects from breast cancer surgery. One of the biggest side effects of breast cancer surgery that has all been but eradicated in the past 20 or 30 years is lymphedema. A profound evolution of treatment has virtually extinguished the condition: radical mastectomy gave way to modified radical mastectomy, and then modified radical mastectomy gave way to lumpectomy, and then sentinel lymph node biopsy replaced axillary lymph node dissection. With sentinel lymph node biopsy, surgeons can selectively do a biopsy on just one or two lymph nodes instead of 20 lymph nodes – thus significantly reducing the incidence of lymphedema.

“Because we’re able to do much less surgery now than we ever did before, we’re seeing much less complications due to surgery,” Iglehart acknowledges. “The field of breast cancer has evolved greatly from the days of radical mastectomies that caused people to really suffer. Once the shift to modified radical mastectomies happened, the complication rates dropped dramatically. And then people started doing lumpectomies, and then sentinel node biopsies over axillary node dissections – overall, it’s remarkable how much less surgical treatment is needed compared to just a couple decades ago.”

Road to personalized medicine

The preoperative, subtype approach to clinical trials along with the recognition of the four distinct types of breast cancer are pushing breast cancer treatment ever closer to personalized medicine.

Thanks to the application of genetics, the subtypes of breast cancer are able to be defined by the presence or absence of the estrogen receptor or the HER2 gene – and the degree of genetic instability that defines the basal-like breast cancer subtype. Ultimately, the subtypes are defined by the targets used in targeted therapy. “We’ve gone from one disease to four in the span of twenty years, each of which is being treated separately and will only subdivide more in the future,” Iglehart says. “As we do fundamental genetic research and uncover the motive pathways of genes in these different disease types, we’ll get better and better at targeting therapy.”

Today the medical community has tackled the low-grade ER-positive disease, and is poised to make progress with the high-grade ER-positive breast cancer, in particular, finding out the growth factor pathways that drive the disease. Iglehart has high hopes for the future that these will be discovered and other small molecule inhibitors and new drugs will be developed against genetic pathways for application to therapy. “I would predict in the next ten years that we’ll see an explosion of new, effective therapies for breast cancer because we’re really poised. We know exactly which diseases we need to make progress in now. Once we figure out the genetics, the treatments should come very quickly.”

Iglehart also has optimism from his own personal studies related to further understanding disease progression. In fact, his group at the Women’s Cancer Program at Dana-Farber/Harvard Medical Center along with part of his specialized SPORE research program played a significant part in advancing the understanding of the triple-negative breast cancer. “I would say the most significant work that I personally have been involved in is the realization that the triple-negative breast cancer is a distinctive subtype and is genetically unstable and has a fundamental defect in DNA damage repair, and have taken that realization forward into a clinical trial.”

Much of the current focus is being directed towards the HER2-positive breast cancer, largely because it’s such an obvious target due to the ability to point to the amplification of HER2 as the driving factor for the development of cancer.

“The biggest target or the most profitable, useful target for HER2-positive breast cancer is going to be a gene called PI3 kinase, a downstream effector that’s right downstream of HER2,” Iglehart explains. “HER2 sits right on the cell membrane and acts with growth factors to receive outside signals that tell the cell to grow. The next gene it encounters as it transmits that signal into the cell is this gene called PI3 kinase.”

It was recently discovered that as many as 30-40% of breast cancers harbor mutations in the P13 kinase gene that activate it – which means it’s always on in HER2 positive breast cancer. Thus, the conclusion is that interrupting it experimentally in HER2-positive breast cells will stop the growth. Today a good number of drug companies are working on making a PI3 kinase inhibitor because it’s such a prime target.

Iglehart’s group is doing a lot of work on PI3 kinase, which was actually discovered in part at Dana-Farber approximately 20 years ago, and there continues to be a significant amount of interest in that gene pathway by a number of investigators at Dana-Farber. Currently his group is conducting an early-phase clinical trial of a PI3 kinase in breast cancer based on their theory that PI3 kinase inhibitors may be substantially helpful in HER2-positive breast cancer.

Apart from the ongoing research and anticipated new drug developments, the study and application of genetics has already begun to revolutionize the understanding and treatment of breast cancer – and has set the arena of breast cancer on an accelerated trajectory in the direction of personalized medicine. “I would say that the prospects look very good for increasing the personalization of medicine in treatment for breast cancer, and I think this is going to happen within probably the next ten years, dramatically changing the outlook,” Iglehart projects.