Since two-thirds of breast cancer is ER/PR-positive, research on new or improved therapies that target hormone receptors is ongoing. A couple of trials recently presented at the San Antonio Breast Cancer Symposium (SABCS) attempt to improve on currently available therapies for women with ER-positive, metastatic breast cancer.

The first trial is one of the more exciting trials presented this year at SABCS, as it improves hormonal therapy for heavily pretreated patients (patients who have received many therapies). This trial was based on the observation that resistance (not responding, either initially or after a period of responding) to hormonal therapy is associated with a tumor using pathways other than the estrogen pathway to survive and grow. One example of this is activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. Afinitor (everolimus), a drug that is currently FDA-approved for renal cancer, targets the mTOR pathway and is classified as an mTOR inhibitor. The BOLERO-2 trial randomized 724 postmenopausal women with ER-positive, metastatic breast cancer whose disease had progressed on Arimidex (Anastrazole) or Femara (letrozole) to Aromasin (Exemestane) with Afinitor or placebo. Arimidex, Femara, and Aromasin are all aromatase inhibitors (AIs), which work by lowering estrogen levels in postmenopausal women. The women who received Aromasin plus Afinitor had a much longer time before their disease progressed (“progression-free survival” or PFS) compared to the women who received Aromasin plus placebo — 11 vs. 4.1 months, respectively. At the present time, the overall survival data are not mature, so it is currently unclear if the women receiving Afinitor lived longer than those receiving placebo. Afinitor did add some toxicity to Aromasin, namely rash, higher blood sugars, mouth sores, diarrhea, fatigue and decreased appetite. A type of pneumonia not due to infection was also seen with Afinitor. These side effects were consistent with previous trials using Afinitor and were generally manageable with holding doses or reducing the dose.

These results are exciting because these women were heavily pretreated and had limited options for further therapy. Over half of the women had received three or more prior therapies. This trial was published in the New England Journal of Medicine, and the data have been submitted to the FDA for possible approval of Afinitor in combination with Aromasin for ER-positive breast cancer. Stay tuned…

Another notable trial presented at SABCS combined two currently FDA-approved drugs for breast cancer: Arimidex and Faslodex (fulvestrant). The idea of combining a drug that works by targeting estrogen receptors (tamoxifen or Faslodex) and a drug that lowers estrogen levels (such as Arimidex) is not a new idea; however, in the past it has not proven successful. A previous adjuvant trial combined Arimidex and tamoxifen and found that the combination was no better than tamoxifen alone — a very disappointing result. One reason for the lack of benefit from the combination may have been that when you drastically lower estrogen levels with Arimidex, tamoxifen acts more like estrogen than an anti-estrogen. Perhaps that issue could be avoided by using a true anti-estrogen such as Faslodex. A subsequent trial, however, combining Arimidex and Faslodex (the Fulvestrant and Anastrazole in Combination Trial, or FACT trial) did not show any benefit to the combination. The study presented at SABCS this year was a Southwest Oncology Group (SWOG) trial, S0226. This was a phase III study that randomized 700 postmenopausal women with metastatic, ER-positive breast cancer to Arimidex alone or with Faslodex. The women on this trial were not allowed to have had any prior chemotherapy or hormonal therapy for their metastatic disease. They were allowed to have had prior tamoxifen or arimidex (or other AI) in the adjuvant setting, but only 40% of the women had received prior tamoxifen, and only 12 women received a prior AI. This is not really typical of the patients in our clinics: most of our patients with ER-positive, metastatic breast cancer have received adjuvant hormonal therapy with either tamoxifen or an AI. On this trial, the patients who received Arimidex plus Faslodex had a longer PFS compared to Arimidex alone (15 months vs 13.5 months) as well as a better overall survival (47.7 months vs 41.3 months). Unfortunately, these benefits in PFS and overall survival appeared to be limited to the women who had not received prior tamoxifen; the women who had received prior tamoxifen did not appear to benefit from the combination.

Faslodex and Arimidex as single agents are both currently FDA-approved for breast cancer. So, is it time to routinely combine them for metastatic breast cancer? Does this represent a new standard? I don’t think so. It’s concerning that these results conflict with the FACT trial results. It’s also bothersome that the benefit in this trial for the combination appears limited to those women who had not had prior tamoxifen. What about our patients who received an adjuvant AI? There weren’t enough of them on this trial to comment. And patients with ER-positive, metastatic breast cancers who have not received adjuvant tamoxifen or an adjuvant AI are a very limited group in the typical breast cancer clinic.

In addition to being used for osteoporosis, bisphosphonates are currently the standard of care for patients whose breast cancer has spread to the bones. These drugs help strengthen the bones and reduce the risk of fractures and pain. Normal, healthy bones are constantly breaking down and then rebuilding. This process keeps our bones strong.

When breast cancer spreads to the bone, however, it can cause the bone tissue to break down too quickly, and the tissue can’t be replaced at the same rate. As a result, the bones may become weak and prone to breaking more easily. This is very similar to what happens to postmenopausal women due to a lack of estrogen. Bisphosphonates work by hindering the cells (osteoclasts) that break down bone tissue. Bisphosphonates that are FDA approved for metastatic breast cancer include Aredia (pamidronate) and Zometa (zoledronic acid), both of which are given intravenously. In non-metastatic breast cancer treatment, oral bisphosphonates may also help prevent bone thinning that can result from treatment with aromatase inhibitors or from early menopause caused by chemotherapy.

Bisphosphonates can have important side effects, including flu-like symptoms and bone pain, particularly with the first few doses. They can also lead to kidney problems. A rare but significant side effect of bisphosphonates is osteonecrosis in the jaw bones (ONJ). This is typically triggered by having a tooth removed while receiving a bisphosphonate. ONJ often appears as an open sore in the jaw that won’t heal. It can lead to loss of teeth or infections of the jaw bone. Most doctors recommend that patients have a dental checkup and have any tooth or jaw problems treated before they start taking a bisphosphonate.

Currently, however, one of the hottest topics in the treatment of breast cancer is the use of bisphosphonates in patients with early stage breast cancer to prevent recurrences. Breast cancer cells stimulate osteoclasts, the cells that break down bone, and these osteoclasts then stimulate the growth of breast cancer cells, creating a vicious cycle. Bone is often the first site of metastatic breast cancer. Theoretically, if bone could be eliminated as a “safe harbor” for breast cancer cells, metastases to bone could be prevented.

Multiple trials were recently presented at the San Antonio Breast Conference in early December that involved the use of bisphosphonates in early stage breast cancer. The first trial presented was the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG-12) which randomized 1,800 premenopausal women whith stage I and II, ER-positive breast cancer who were being treated with ovarian suppression (with Zoladex (goserelin)) to one of 4 arms:
1. Tamoxifen for 3 years
2. Tamoxifen + Zometa every 6 months for 3 years
3. Arimidex (anastrazole) for 3 years
4. Arimidex + Zometa every 6 months for 3 years

Only neoadjuvant (preoperative) chemotherapy was allowed; therefore only a small percentage of the patients received chemotherapy. While there was no difference between tamoxifen and Arimidex, the use of Zometa did reduce the risk of recurrence and death, mostly in the women who were over the age of 40 (the group in which ovarian suppression with zoladex was most likely to truly produce a postmenopausal state). There were no reported cases of ONJ or renal failure.

While these results are very exciting, it is a bit difficult to extrapolate them to patients treated in a typical fashion in the US. For example, most premenopausal patients in the US receive neoadjuvant or adjuvant (post-operative) chemotherapy rather than ovarian suppression to treat their breast cancer. Also, most patients in the US receive adjuvant endocrine therapy for at least 5 years, not 3.

A second trial presented was the ZO-FAST trial. In the ZO-FAST trial 1,060 postmenopausal women with hormone receptor-positive breast cancer being treated with adjuvant Femara (letrozole) 2.5 mg orally daily were randomized to receive Zometa every 6 months for 5 years starting with the Femara (the immediate Zometa group) or Zometa added only when bone mineral density scores decreased to a certain level (the delayed Zometa group). In women who were postmenopausal for longer than 5 years or who were more than 60 years old at study entry (patients who may be in a particularly low estrogen environment), immediate use of Zometa reduced the risk of recurrence and prolonged survival. There were 3 confirmed cases of ONJ on this trial.

Another trial presented was NSABP Protocol B-34, which differed from the first two trials in that it used the oral bisphosphonate clodronate. This study randomized over 3,000 patients with stage I-III breast cancer to clodronate for 3 years or placebo either alone or in addition to adjuvant chemotherapy or hormone therapy. Although there was no benefit for clodronate in the overall population, there did appear to be a benefit in the older patients, once again suggesting that bisphosphonates may be most useful in postmenopausal women.

Finally, the GAIN trial, using a different oral bisphosphonate (ibandronate) was also presented. Patients receiving adjuvant epirubicin, Cytoxan (cyclophosphamide) and Taxol (paclitaxel) were randomized to receive either ibandronate vs placebo. As was seen in NSABP B-34, there was no benefit in the overall population. The older patients appeared to have a better result with ibandronate, although this benefit wasn’t statistically significant.

So, how do we interpret these trials? Well, I think it’s fair to say that in the future, bisphosphonates will likely play a role in the adjuvant therapy of early stage breast cancer. However, there are still many questions remaining, including the optimal bisphosphonate (IV or oral) as well as what group of patients appears to benefit the most. At the present time, it appears that the benefit may be limited to postmenopausal women. Perhaps this is because postmenopausal, estrogen-deprived bone is more vulnerable to metastases from breast cancer, while healthier, premenopausal bone puts up more resistance to metastases. We will undoubtedly be seeing more data in the future that will clarify how these drugs can optimally be used.

Studies have consistently shown a “linear dose-response” relationship between alcohol intake and breast cancer risk in women. This basically means that the more alcohol you consume on a daily basis the higher your lifetime risk of breast cancer. The exact mechanism by which alcohol leads to an increased risk of breast cancer is unknown however one of the most prominent theories is that alcohol leads to increased estrogen levels in women.

Most past studies however have primarily shown an increased risk of breast cancer in women who drink at least one alcoholic beverage per day and the effect of lower amounts of alcohol intake was less clear and less consistent. Also the studies didn’t look at patterns of drinking, such as binge drinking or regular, low intake, nor did they look at alcohol intake at different times in a woman’s lifetime.  A study that looked more closely at these issues has been recently published and helps clarify the risk. Continue reading →

The pursuit of cure for many patients with breast cancer involves mastectomy, the medical term for surgical removal of the breast. Mastectomy is a necessity for some patients, and a preference for others. Breast conservation surgery is often not feasible among patients with large breast cancers or tumors that are deeply invasive. As well, some patients may desire to undergo mastectomy rather that breast conservation therapy as a personal decision or in light of genetic circumstance. For example, patients who are carriers of the breast cancer susceptibility genes may opt for bilateral (both left and right breast) mastectomies in order to decrease the risk of subsequent breast cancers.

After mastectomy, radiation therapy may play an important role in preventing cancer recurrence. Radiation therapy is referred to as an “adjuvant” therapy in this setting – meaning that it serves as an “adjunctive” measure towards cure. While surgery is often the most important aspect of gaining control of breast cancer, adding radiotherapy can significant reduce the risk that micrcoscopic cancers cells which may been left behind at the time of surgery, can grow, divide, and develop into a cancer recurrence.

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Survival statistics for women with breast cancer have improved dramatically in recent years, resulting in the majority of newly diagnosed breast cancer patients surviving more than 5 years after their diagnosis. In fact, in 2010, the American Cancer Society estimated that there are 2.5 million breast cancer survivors in the US.

This is obviously excellent news, but it makes it very important that patients and their primary care providers be able to recognize and treat any chronic (side effects occurring during and persisting after treatment) and late (side effects that appear after the end of therapy) consequences of cancer therapy. In 2006, the Office of Cancer Survivorship (OCS) was formed at the National Cancer Institute, reflecting an increased emphasis on the needs of a growing population of cancer survivors. Some of the most prominent issues facing breast cancer survivors include the following:

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In the past, oncologists were primarily concerned with whether a breast cancer was hormone receptor-positive (ER+) or negative and whether it overexpressed HER2 or not. And the vast majority of women with early stage breast cancer were given chemotherapy to try to prevent their breast cancer from coming back, regardless of hormone receptor results or lymph node status. Unfortunately, many of those women would likely have been cured without chemotherapy, but we didn’t have any reliable way to distinguish who needed chemotherapy and who did not.

The good news is that we really have come a long way in recent years in developing ways to make this distinction, spare many women the side effects of chemotherapy and truly personalize treatment decisions. This is very exciting, because more than half of the women in the U.S. diagnosed with breast cancer have ER+, lymph-node-negative cancer. New tests that are now available identify genetic or biological factors that drive each individual woman’s particular cancer, allowing their oncologists to personalize treatment in a way we were unable to do in the past. Multiple assays are commercially available to look at the genes in an individual cancer. In the US, Oncotype DX is the most commonly used.

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Herceptin (Trastuzumab), the antibody against the HER2/neu protein over-expressed in about 20-30% of breast cancers, has been shown to reduce the risk of recurrence and death from HER2-overexpressing breast cancer in several, large randomized trials and as a result has become a standard part of adjuvant therapy for such patients with early stage breast cancer. However, one group of patients that was excluded from all of the large, randomized trials was patients with node-negative tumors that were 1 cm or smaller. This group of patients is presumed to be at lower risk or recurrence and death than their counterparts with larger or node-positive tumors, and the role of adjuvant Herceptin-based chemotherapy is therefore uncertain and controversial. Does biology (being HER2-positive) trump size? Or does size still matter?

All of the large, randomized adjuvant herceptin trials included some form of chemotherapy (none gave Herceptin alone), which increases the potential risks. Is there a tumor size in which the outlook without adjuvant chemotherapy and Herceptin is so good that the risks of therapy outweigh the potential benefits? These are very important questions and issues to resolve, because the incidence of very small breast cancers has increased in the past two decades, due to the prevalence of mammographic screening programs. This group of patients, however, likely remains too small for randomized trials to be performed. Therefore, we need to rely on other sources of information to make patient care recommendations.

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Radiation therapy plays an important part in the care of many breast cancer patients. The term breast conservation therapy (BCT) is a combination of breast conserving surgery (also referred to as lumpectomy) and radiation therapy. It is only in rare circumstances that breast conservation surgery is undertaken without planned radiotherapy to follow. For patients that undergo mastectomy instead of breast conservation surgery, radiation therapy may still play an important role, but it is not of universal benefit as it is after breast conservation surgery.

Many options exist for radiation therapy after lumpectomy. “Conventionally fractionated” whole breast irradiation remains the standard treatment in the United States and is the treatment received by most women after lumpectomy. “Conventionally fractionated radiation” refers to dividing the total radiation dose into small amounts which are delivered on a 5-treatment per week basis, for a total of five to six and a half weeks. The entire breast is treated for the majority of the treatment course. Near the end of the treatment, only the specific region of the breast which formerly contained the tumor is targeted, typically for the last 5 treatments; this more focused component of the treatment is referred to as a “radiation boost.”

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The prognosis of IBC has greatly improved with the adoption of multimodality therapy that includes systemic chemotherapy along with surgery and radiation therapy. In the past, when surgery was the sole treatment, IBC had an extremely poor prognosis, with very low rates of survival. Perez and colleagues conducted a retrospective analysis of 179 patients with IBC and found that patients who were treated with multimodality therapy that included chemotherapy, surgery, and radiation therapy had a better 5 and 10 year disease-free survival (DFS), compared to those not treated in this fashion. Multimodality therapy led to a 10 year DFS of 35%, compared to 24% with radiation and surgery, and 0% for radiation alone or radiation plus chemotherapy without surgery. Similarly, 20 years of experience treating 178 patients with IBC at the University of Texas MD Anderson Cancer Center revealed that a multimodality approach led to 28% remaining disease free past 15 years, compared to less than 5% of patients treated with a single modality.

At the present time, the standard therapy for IBC per the National Comprehensive Cancer Network (NCCN) guidelines is neoadjuvant chemotherapy (chemotherapy given before surgery) with an anthracycline based regimen with or without a taxane. If the tumor is HER2-overexpressing, Herceptin (trastuzumab) should be incorporated into the regimen. Mastectomy with an axillary node dissection followed by radiation therapy and endocrine therapy (if the tumor is hormone receptor-positive) is then recommended for patients whose tumors respond to chemotherapy.

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