News Wrap-Up from San Antonio

For this final report from the 2011 San Antonio Breast Cancer Symposium, we are going to focus on the larger themes or take home messages, rather than on individual studies.  The big news has been summarized in previous reports, and we will be providing additional information and perspective in the next few weeks.   Here are some of the important things to think about the current state of breast cancer research.

Cancer is Complex, and Science Really Matters
There is no question that research is yielding extraordinary new knowledge about the biology of cancer cells – how they begin, divide, grow and spread.  It has become apparent, though, that the more we discover about the workings of both normal and abnormal cells, the more we become aware of the complexity of cancer.  Understanding and targeting the specific mutations that allow cancers to grow and spread is without a doubt the future of cancer treatment, but is now clear that this is not going to be a simple process.  Take these two examples from studies presented at San Antonio.

HER2-positive Breast Cancer Treatment:  The discovery that approximately 25% of women with breast cancer overexpress the HER2 gene, and the newly-developed ability to block that expression, is one of the most important advances in breast cancer treatment in the last two decades.  HER2 is what is known as a "driver mutation," meaning that breast cancers are "addicted" to the protein it produces.  Deprive the cancer cells of HER2, and they can't grow.  The advent of Herceptin (trastuzumab) has significantly improved outcomes for women with both early stage and advanced HER2-positive breast cancer.  Lurking behind virtually every successful cancer treatment, however, is the problem of resistance.  Researchers often describe cancer cells as "smart," meaning that they have a remarkable ability to adapt, mutating in ways that allow them to overcome or bypass the efforts to stop their growth and division.

Understanding drug resistance really means understanding those complex biologic mechanisms that lead to these changes or adaptations on the part of cancer cells.  Researchers now know, for example, that HER2 is really one of a family of four related genes that interact with each other.  If you block HER2 with one drug, its relative HER3 can also signal cancer cells to grow.  By deciphering these complex pathways, researchers have figured out that is critical to target both genes in order to effectively block the growth of breast cancer cells.  The result is a new agent, pertuzumab, which provides what is known as a "dual blockade" of the HER2 gene amplification and is likely to become a very important part of the approach to treating HER2-positive cancer.

Cancer and its Environment:  In this case, the environment doesn't mean the things we eat or drink or the chemicals to which we are exposed.  In recent years, researchers have becoming increasingly aware that cancers are not "islands."  They interact with, and in many ways depend on, the microenvironment in which they live to grow and to spread.  Cancer cells need nourishment and a blood supply.  They also have complex relationships with the body's immune system, sometimes evading it and other times actually taking over a part of it.  A key scientific study done with mice provides intriguing evidence about one potential aspect of this relationship between cancer cells, the environment, and the immune system.  The study showed that one type of macrophage (a white blood cell that is a key player in destroying foreign invaders in the body) actually seems to protect cancer cells and promote metastases in mice.  If you use a drug to deplete these cells, the number of metastases drops – though the primary tumor doesn't shrink.  This kind of science offers very interesting clues about ways in which new treatments could be developed based on new understanding of how cancers interact with the immune system and other parts of their environment.

Drug resistance and metastasis – two of the biggest, toughest problems in treating breast cancer, and every cancer.  The answers require better understanding of the remarkably complex biology of our cells.  Science matters.

New Attention to Side Effects
A significant percentage of post-menopausal women taking aromatase inhibitors (AIs) for their breast cancer stop taking their drugs because of the side effects.  The numbers vary, but the range is between 10-30%.  Every study of AIs shows that these drugs do cause side effects – most notably, serious aches and pains, hot flashes and vaginal dryness – and virtually every one concludes that these toxicities are “acceptable and well-tolerated by patients.”  But those patients taking AIs seem to disagree.  AIs work really well to prevent recurrences of breast cancer and to treat advanced breast cancer.  New studies also demonstrate taking them can reduce the incidence of invasive breast cancer in women at high risk by 50-67%, but these results have generated little enthusiasm among women, because the considerable side effects make taking the drug a burden.

There is clearly a gap between how doctors record and analyze side effects and how patients perceive them.  Thankfully, the need to pay more attention to side effects, and to ask patients what they are experiencing, is becoming more prevalent.  Patient reported outcomes are gradually gaining acceptance as valid and important sources of data, and a basis on which to make treatment decisions.  Doctors are recognizing that there may be a difference between the note they write in a chart and what is actually happening with the patient.  

The AI experience is a good example of this phenomenon, but it applies to other situations as well.  As new agents are introduced, the options available for treating patients increase.  Some of the benefits of these different treatments are measured in relatively small increments – improved response rates, better progression-free or overall survival.  If a new treatment makes a huge difference in survival but has more side effects, it may be worth it to many patients – but what of treatments that only make a small difference?  How do you assess greater side effects, and potentially a lower quality of life, compared to a few extra weeks of months of life?  These are issues that have moved more to the forefront of breast cancer research and are actively included in the discussion of clinical trial results.  That is definitely a form of progress.

When is Less More?
“Having cancer in your body is bad, getting rid of it is good.”
“There is no such thing as ‘a little cancer’ or a harmless cancer.”

That is what we have always thought, but new techniques for detecting very tiny cancerous and precancerous conditions, and for characterizing those cells, suggest otherwise.  Researchers are now questioning whether every tiny, low-grade prostate cancer needs to be treated.  They are looking at the management of microscopic metastases in the lymph nodes of patients with certain thyroid cancers to determine if they really require intervention.  The concept of "watching and waiting" is becoming an established part of managing some cancers.

The same principles may hold true for DCIS, ductal carcinoma in situ of the breast.  There are increasing indications that some of these early or precancerous conditions will not progress to invasive breast cancer and do not need to be treated as if they were invasive.  The question is – which ones?  Again, the answer lies in better understanding of the biology of the disease and the ability to develop genetic profiles that will predict the behavior of individual tumors.  The announcement of the new OncotypeDX test for DCIS represents a major step in that direction, but a first step.  The whole concept of what makes a cell cancerous, of what factors drive growth, invasion, and metastasis is just beginning to emerge as critical.  It is difficult for patients with DCIS to think about not treating their condition, but if our knowledge of cancer can advance to the point where we truly can predict which of these tumors will become invasive, it could spare many women from surgery and radiation therapy which are now the standard.  The whole idea of examining when “less is more” is becoming a very important facet of how we think about cancer and its treatment.