Published April 16, 2014 By Dr. Susan Love

The American Association of Cancer Research (AACR) is the professional organization for scientists working on cancer. The annual meeting is large, international, and usually a bit overwhelming. The meeting is focused on all types of cancer. Sometimes the talks are quite basic about how cancer is initiated or how the immune system seems to work. Other talks are more clinical, usually with early data from phase one or two studies rather than from phase three studies (which are needed for drug approvals.) This is one of my favorite meetings on the annual calendar because it is the best place to get a glimpse into where things are going in cancer research and what the new breakthroughs are likely to be. This year was a good example. It is well accepted that we all have mutations in our cells and acquire more mutations the older we are. One example mentioned was the bone marrow where the blood cells are formed. The blood stem cells divide once a month! Every time cells divide, they have the opportunity to make an error (like getting a “typo”), which is then propagated on to the next generation of cells, ad infinitum (or until you die.) Any one of these typos or combinations of typos could result in a cancer. Professor Jane Visvader, Joint Head of the Division of Stem Cells and Cancer and the Breast Cancer Laboratory at The Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, talked about the breast stem cells. The breast is one of the only organs that is not developed at birth. In an infant, there is a nipple and behind it, stem cells that have the potential of developing into a breast. I liken the undeveloped breast to the toys we had as kids that came as a capsule containing a compressed foam animal, which emerged when you let the capsule dissolve in water. When puberty unleashes its hormones, a breast emerges where previously there was only a nipple. These stem cells are responsible for forming the whole breast, making it ready to make milk, and reforming it after the lactation period is over. Breast stem cells are prime targets for mutations that could lead to cancer years later. There is a lot of work going on to determine whether all the kinds of breast cancer can come from a mutated stem cell or whether the daughter stem cells (e.g., cells resulting from the replication and division of a single parent cell) develop different mutations which then lead to different kinds of cancer. In addition, the cellular neighborhood also may influence what kind of cancer develops. The one thing Prof. Visvader mentioned that may make it to the clinic sooner rather than later is RANK-RANKL. This is a marker of luminal progenitor cells (source of luminal and basal breast cancers including those of BRCA 1 / 2 carriers) in the human breast. This marker is also involved in bone metabolism and bone metastases from breast cancer as well as in the immune cells. A new drug for osteoporosis, denosamab, works by blocking RANK and may have potential for chemoprevention for both mutation carriers and other women. Much of what you read in the media regarding cancer refers to “precision medicine” or “personalized medicine.” This concept is based on the data from the Tumor Genome Atlas Project (TCGA), which sought to map the DNA mutations in all cancers. The theory was that if we could map the mutations in your cancer, we could find a treatment that blocked that gene or neutralized its protein and stop the cancer in its tracks. This has worked in some cancers; i.e., HER-2/neu breast cancer and BRAF positive melanoma, but more often than not when we block one pathway, the tumor cells just take a detour or alternative route and the cancer recurs. The unofficial theme of this meeting seemed to be “too many targets,” (i.e., pathways or mutations)! This doesn’t mean that researchers will abandon this approach entirely but rather, that it is now clear that we are going to need more than “Precision Medicine” to eliminate cancer. Lest you become depressed, however, there IS a new direction that was getting all the attention at AACR: the immune system! Although the public usually thinks of the immune system as a barrier to cancer, the scientific community has not. Now that belief has changed as researchers have begun to explore how the immune system may be harnessed to prevent or control cancer. In order for a cancer to develop, it has to have a way of keeping the immune cells at bay by either turning off the immune cells or blocking them. If that is possible, it should be possible to turn the immune system back on. The trick, of course, is to program the immune system to attack just the cancer cells and NOT the normal ones. The early examples of this type of approach focus on prevention of recurrence, with examples such as the prostate drug Provenge®, and two ongoing studies looking at preventing DCIS from becoming invasive by employing a HER2/neu vaccine. A second approach is focused on using the immune system in the treatment of cancer. In order to grow and proliferate, tumor cells have to get past the immune system. They do this by keeping the T cells (a type of white blood cell that plays a central role in immune response) from multiplying or becoming active. A new approach that has had some early success is to block the cyclin-dependent kinases 4 and 6 (CDK4/6). In essence, this approach releases the “brakes” that the cancer cells put on the ever-vigilant T cells, allowing the T cells to go to town. The first drug, developed against melanoma, is ipilimumab and it, along with its cousin nivolumab, led to deep tumor regression in one-third of patients with stage IV melanoma. In breast cancer, the big news was the results of the Paloma trial. This study compared CDK 4/6 with the drug letrozole (hormonal therapy) to letrozole alone in women with stage IV breast cancer that was ER-positive and HER2 negative. The combination of the hormone manipulation and the immune manipulation resulted in 80% of women with untreated metastatic disease having stable disease and an increase in relapse-free survival of 20 months. It is too soon to say whether there is an increase in survival overall. While this first study of immune modulation was in women with hormone positive metastatic disease, there is no reason that it, or a variation thereof, will not be tried in women with HER2 positive or triple negative tumors. Another immune approach discussed at AACR is checkpoint inhibition. CTLA-4 blockade enhances tumor specific immunity and has also shown benefit in melanoma. It works along with a second set of inhibitory molecules PD-1 that attach to ligands (attachment points) on the tumor cell itself. This is another way the tumor cells convince the immune system (T cells) to leave them alone. By using antibodies to these molecules, the tumor can be stopped from turning off the T cells. Combining the two approaches gives an even more astonishing result, with almost 100% of tumors responding by week ten. This area of checkpoint inhibition will result in many new therapies. Finally, and very interesting to me, was the panel on the microbiome. Just as cancer researchers have focused on the tumor cells and neglected to pay attention to the immune system until recently, they have also avoided thinking about the vast numbers of bacteria and viruses that live in our bodies. I have written about the Dr. Susan Love Foundation for Breast Cancer Research’s exploration of the biome of the breast, but this AACR panel focused mostly on the colon. In this session, the most interesting observation was not only that the microbiome is involved in whether you get cancer, but it also affects how well certain drugs work! This area of exploration is just beginning, but watch this space as it will become increasingly important in the future. These are just some of the exciting highlights of AACR 2014, and by the last session, I was ready to head home with my head full of new ideas. In late May, I will head to Chicago for the American Society of Clinical Oncology, which focuses on treating cancer and as such, is less hypothetical and more focused on new treatments. These two meetings, along with the San Antonio Breast Cancer meeting in December, are where I go to figure out where research is going and what is next in breast cancer treatment. And I promise to “keep you all abreast” of what I find out!

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