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January 2012 Ask the Expert: Targeted Therapies and Personalized Medicine

The decision about whether to use hormonal therapy or HER2-targeted therapies is personalized to the type of breast cancer you have. If the cancer tested positive for hormone receptors, HER2 receptors or both, you have important information about how the cells are growing and multiplying. Hormonal therapy or HER2-targeted therapy can target these cancer cells, slowing or stopping their growth and reducing recurrence risk.

During the month of January, Living Beyond Breast Cancer expert Robert A. Somer, MD, answered your questions about targeted therapies and how they are used to personalize breast cancer treatment.

Question: My question is about tamoxifen. I guess the standard regimen is a five-year program. Why is it five years?                              

Dr. Somer: The clinical trial NSABP B-14 enrolled 2,843 women with estrogen receptor-positive, lymph node-negative breast cancers and assigned them to one of two treatment groups by random computer selection: tamoxifen for five years or a placebo, an inactive substance or sugar pill, for five years. Then, 1,172 women who were treated with tamoxifen and remained disease-free after five years were randomly re-assigned to receive either another five years of tamoxifen or five years of placebo.

Results showed that five years of tamoxifen not only increased the amount of time women remained free of cancer, but also increased overall survival. It also lowered the risk of breast cancer in the opposite breast by about half. Taking tamoxifen for more than five years did not appear to provide additional benefit and created a major increased risk of blood clots eand endometrial (uterine) cancers. So, five years became the standard of care. Because of better understanding of treatment over time, results of this trial are a major source of discussion.

Another large trial, the ATLAS trial (Adjuvant Tamoxifen, Long Against Short), is comparing five years of tamoxifen to 10 years. This trial, which is still active, is expected to evaluate almost 10 times more women than the B-14 trial. The final results have not yet been presented to the public, but we hope that we will be better able to answer your question through the scientific results of a clinical trial.

Question: Is there anything new with these targeted strategies and breast cancer vaccines?

Dr. Somer: With the FDA approval of quadrivalent (Gardasil) and bivalent (Cervarix) to prevent cervical cancers, coupled with the FDA approval of sipuleucil-T (Provenge) for the treatment of prostate cancer, cancer vaccines have made major headlines in the media over the last few years. There are currently over 25 clinical vaccine trials specific to breast cancer treatment. Many of them take advantage of the fact that breast cancer cells may have a protein on them that we can target. Some of them are pure "vaccine" trials, and some incorporate chemotherapy.

Question: This is about targeting the tumor. Is there much research being done on matching drugs to specific subtypes of breast cancers? For example, lobular breast cancer and X drug.

Dr. Somer: There is a tremendous amount of research that looks at taking advantage of cancer cell characteristics (compared to normal cells) and looking for a protein (something found on the surface of the cancer cell, or inside the cell) that we can "target."

The first "targeted therapy" was over a hundred years ago when they removed the ovaries in premenopausal women with metastatic breast cancer and noted that the breast cancer improved. This led to the discovery of the estrogen receptor (ER). Treatments were then developed such as tamoxifen that target the ER and the aromatase inhibitors which lower estrogen levels.

The same concept is currently being applied to other targets, such as HER2 receptor. Although we tend to classify cancers into about 5 different categories, we realize that we are only seeing the tip of the iceberg and there are probably hundreds of different subtypes. Why do some ER+ cancers benefit from chemotherapy, while others do not? Why do some people do better than others? These are questions actively being worked on in the context of clinical trials and research.

Ductal cancers and lobular cancers are named by the way they look under a microscope. What makes them behave a certain way, regardless of what they look like, and how we can predict better response to treatments are the questions currently being studied.

Question: I had a basic question in terms of aromatase inhibitors. If you’re faced with the choice of those three drugs, how do you know which one is personalized and best for you?

Dr. Somer: There are currently three aromatase inhibitors (AI) approved: anastrazole (Arimidex), exemestane (Aromasin) and letrozole (Femara). These are approved for use in post-menopausal women with breast cancer.

In metastatic disease (when the cancer has traveled to another body part), any one of these can be used, and there is evidence that exemestane can be used after anastrazole or letrozole.

In the adjuvant setting (giving these medications after surgery to reduce risks of recurrence), anastrazole or letrozole are typically given up front if your oncologist chooses to start with an aromatase inhibitor.

Based on findings from clinical trials, if you have previously taken tamoxifen, then exemestane can be given after 2-3 years of taking tamoxifen; anastrazole can be given after 2-3 years of taking tamoxifen; or letrozole can be given after five years of taking tamoxifen. The clinical trial NSABP B-42 is currently investigating whether or not continuing an additional five years of an aromatase inhibitor after having already received five years of an aromatase inhibitor will improve breast cancer outcomes, regardless of which AI women have taken.

Unfortunately, because they lower estrogen levels in the body, all of these agents have side effects which affect the bones, joints and lipid/cholesterol levels in the blood. Your physician will need to carefully monitor you while on these agents. All three of these agents appear to be very similar in activity and toxicity, and one in particular may not be better for you than another.

Question: Are there any new hormone therapies on the horizon?

Dr. Somer: Although there are no "new" hormonal therapies that have been developed recently, there has been interest and growing knowledge on how to make a cancer that no longer responds to hormone treatment respond to hormonal therapy again, as well as how to optimize hormonal therapies to make them work better and longer.

For example, in order to overcome resistance to hormonal therapy, researchers are studying how to give estrogen back to women (!) for a short time and then resume antiestogen therapy.

Several presentations last month at the San Antonio Breast Cancer Symposium focused on optimizing hormonal therapy. In the BOLERO-2 trial (Breast Cancer Trials of Oral Everolimus 2), women with advanced breast cancer were randomly selected to receive exemestane (an AI) alone or in combination with everolimus, a drug that targets a protein called mTOR. On average, the combination treatment more than doubled the time it took for the cancer to worsen.

Another trial combined anastrazole with fulvestrant (both hormonal treatments). Women who took both medicines together lived more than six months longer than women who took the medicines one after the other.

These clinical trials and others are improving our hormonal therapy strategies.

Question: I will take tamoxifen for stage IA lobular carcinoma (following lumpectomy, chemo and radiation). I also have LCIS. Does the tamoxifen reduce the risk of a second breast cancer from the LCIS?

Dr. Somer: Absolutely. In fact, the risk of a stage IA invasive breast cancer recurring in the future is lower than your risk of being diagnosed with a new breast cancer. LCIS is not a cancer diagnosis, but it identifies a person who is at risk of developing breast cancer now or in the future. The presence of LCIS increases your risk for breast cancer over that of an average woman by about 1 percent per year over the next 25-30 years. Of course the vast majority of women with LCIS never get breast cancer, but if it does occur, it can happen in either breast.

The Study of Tamoxifen and Raloxifene (STAR) was a breast cancer prevention clinical trial designed to determine whether raloxifene (Evista), an osteoporosis prevention medicine, is as effective as tamoxifen in reducing breast cancer risk with fewer side effects. The trial began enrolling participants in July 1999 and completed enrollment in November 2004 with 19,747 postmenopausal women at increased risk of breast cancer. About 9 percent of the women who joined STAR reported a previous diagnosis of LCIS. Both medicines reduced the risk of breast cancer by 56 percent! Even though this is a dramatic reduction, it is very important to continue screening for breast cancer while on these agents.

Question: Is there anything new about immunosuppressants used for autoimmune diseases and their effect on breast cancer?

Dr. Somer: There is a lot of information about the relationship between immunosuppression and cancer (and yes, there are some cancers that can develop from immunosuppression), but the link between immunosuppression and breast cancer is controversial. In fact, a recent clinical trial using an immunosuppressant HELPED women with breast cancer. Updated findings from the phase III Breast Cancer Trials of Oral Everolimus (BOLERO-2) study confirm dramatic improvement in the amount of time women with metastatic breast cancer remain without disease progression when the immunosuppressant agent everolimus (Afinitor) is combined with the hormonal therapy exemestane (Aromasin). Women who received the everolimus/exemestane combination remained without disease progression more than twice as long as those who received exemestane alone.

Question: How do you think zoledronic acid (Zometa) and the bisphosphonates will affect long-term use of aromatase inhibitors?

Dr. Somer: Many clinical trials have addressed the relationship between zoledronic acid and breast cancer recurrence. Other trials address whether this agent and/or other bisphosphonates (medicines that make bones healthier) can prevent treatment-induced bone loss. Postmenopausal breast cancer patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid is known to maintain bone health.

The ZO-FAST trial published last year in Annals of Oncology randomly assigned 1065 postmenopausal women who were taking letrozole (Femara), a medicine that lowers cholesterol, to immediate zoledronic acid versus delayed treatment. After following the women for three years, researchers concluded that immediate zoledronic acid was more effective at preserving bone health during letrozole treatment. It showed benefits in terms of breast cancer outcomes, too (see more below).

The Z-FAST trial published two months ago in Cancer was smaller but just as positive. Researchers randomly assigned 602 postmenopausal women with early-stage, hormone receptor-positive breast cancer receiving adjuvant letrozole (a medicine that lowers estrogen levels) to immediate or delayed-start zoledronic acid (4 mg intravenously every six months) for five years, with the hope that bone density would be higher in the group that was treated earlier.  The women who received immediate zoledronic acid experienced a significant increase in bone mineral density , and long-term administration of letrozole and zoledronic acid together was well-tolerated.

Zoledronic acid had been reported to have anticancer properties for years, but it had never been studied over time in survivors of early-stage breast cancer. The ABCSG-12 trial attempted to answer the question as to whether adding zoledronic acid to a combination of either goserelin (Zoladex) and tamoxifen or goserelin and anastrozole (Arimidex) would be beneficial in premenopausal women with endocrine-responsive early breast cancer. Researchers randomly assigned 1803 women to receive goserelin plus tamoxifen or anastrozole with or without zoledronic acid every six months for three years. After following up for four years, researchers concluded that adding zoledronic acid to adjuvant endocrine therapy improved the time premenopausal women with estrogen-responsive early breast cancer remained disease-free , no matter whether they received tamoxifen or an aromatase inhibitor!

A more current trial that has been completed but not yet reported is SWOG-0307, which evaluates zoledronic acid compared to the bisphosphonates, clodronate (Bonefos) or ibandronate (Boniva) to see if it is better at preventing or delaying bone metastasis.

Finally, denosumab (Prolia) was FDA approved in September 2011 to increase bone mass in patients at high risk for fracture such as women on adjuvant aromatase inhibitor therapy for breast cancer. So, I do think it is becoming easier to support bone health, and our previous concerns are being addressed through many research trials.

Question: How does alcohol consumption interact with docetaxel (Taxotere) and cyclophosphamide (Cytoxan)?

Dr. Somer: Although taxanes, the class of medicines that Taxotere and paclitaxel (Taxol) are a part of, affect liver enzymes which are monitored during chemotherapy, there is no bad "interaction." There is no known interaction with cyclophosphamide, either. If the liver function tests (LFT's) start trending up, your oncologist may ask you to limit alcohol, acetaminophen or other medicines/supplements that are cleared by your liver.

This question brings up a few issues surrounding alcohol use and its relationship to breast cancer and treatment. It is well known that excessive alcohol consumption is directly related to increased risk of breast cancer. Behavioral modification is extremely important, not only to prevent breast cancer, but also to reduce risk of recurrence once you are diagnosed. A healthy diet, exercise program and non-excessive alcohol use will translate into better breast cancer outcomes! Also, alcohol consumption can trigger hot flashes, a side effect many women have while on chemotherapy and hormonal therapies. It is okay to have some alcoholic beverages, but realize that moderation is important.