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Reduction in surgery, evolution of systemic therapies highlight recent treatment
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The following transcript comes from a roundtable discussion about developments in breast cancer held during the HemOnc Today section editors’ retreat on May 21.
Edith A. Perez, MD, director of the breast cancer program at Mayo Clinic in Jacksonville, Fla., a member of HemOnc Today’s Editorial Board and a member of the program committee for the HemOnc Today Breast Cancer Review & Perspective Meeting, led the discussion.
Other roundtable participants included Harry S. Jacob, MD, FRCPath(Hon), chief medical editor of HemOnc Today; Laurence Boxer, MD, professor and director of pediatric hematology/oncology at the University of Michigan Medical Center in Ann Arbor; Munir Ghesani, MD, an attending radiologist at St. Luke’s-Roosevelt Hospital Center and Beth Israel Medical Center, and an associate clinical professor of radiology at Columbia University College of Physicians and Surgeons; and Gregory M. Vercellotti, MD, a professor in the division of hematology-oncology-bone marrow transplant at the University of Minnesota.
Dr. Perez: Breast cancer survivorship has improved over the last 20 years, though it is felt to be secondary to enhancements in early detection, as well as therapy.
I would like to briefly explore five different topics that impact survival improvements. These include diagnosis and diagnostic studies, surgery, systemic therapies and survivorship.
Diagnosis
Dr. Perez: Mammography remains the mainstay for public health screening in the setting of breast cancer, but there continues to be some disagreement among the guidelines available related to the timing of initiation of mammographic screening, as well as the frequency of screening.
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After reviewing all of these different guidelines, most experts have concluded it’s appropriate to make a standard recommendation for general public mammographic screening starting at age 40 years, and on a yearly basis after that. The upper age limit for screening mammography is unclear, but the general feeling is that, as long as a woman has an expected life of 5 years due to other comorbid conditions, screening mammography is an appropriate tool to utilize.
One improvement in this area has been the introduction of digital mammography screening in most centers in the United States. Data suggest digital mammography is better than the older mammography, especially in premenopausal women.
Most centers have moved to the digital mammography model because of the ease of storage of materials, and also the transportability of the general materials compared with the older films.
In terms of screening, there are two other areas that are evolving: MRI and molecular screening.
Diagnostic studies
Dr. Perez: There has been an effort by the American College of Pathologists to develop guidelines for pre-analytical variables as tumors are excised and sent to the pathology department that may have an impact in optimizing the immunohistochemistry and gene studies that are done in tissues. There has been a great improvement that hopefully will be incorporated by many sites in the United States.
Additionally, the American College of Pathologists has established quality-assurance programs for reading of ER, PR receptor and HER-2.
Because this is such a core portion of appropriate management of patients with breast cancer, sites should have quality-control programs once every 6 months. That should be part of what we expect all of our hospitals to go through. But right now, pathologists’ groups have to pay the American College of Pathologists to participate in these programs. And only about 85% of pathology groups that I know of participate in quality assurance. This is an area in which we can do a lot better.
Surgery
Dr. Perez: We are doing less aggressive surgery for breast cancer compared with 20 years ago. We’ve moved from the model of everybody requiring a mastectomy to one of lumpectomy and radiation therapy for appropriate patients. Now we’re moving into the area of minimizing the extent of axillary dissection.
First, we were doing full axillary dissection of the three levels. Then we went to two levels. Then we went to the sentinel node detection. Now we have data demonstrating that for some subtypes of breast cancer — specifically postmenopausal women with ER-positive breast cancer — even if there’s an isolated sentinel node that’s positive, full axillary dissection appears not to be necessary. So the morbidity of surgery has continued to decrease in the setting of early diagnosis of breast cancer.
As part of local therapy — which includes surgery and radiation therapy — the traditional radiation model has been to administer external beam radiation for 6 weeks. Newer research has demonstrated that administering radiation over a 3-week period appears to be equivalent in efficacy to the 6-week period, lowering costs with no detrimental effect on local recurrence or cosmesis.
Another area of significant interest is whether we can shorten the radiation treatment from 3 weeks to a few days. That can be accomplished by a variety of technologies.
Ongoing clinical trials are being conducted in a prospective fashion comparing different modalities. But brachytherapy and MammoSite have come to be used routinely in the United States, with guidelines also available for best patient selection for these technologies.
Systemic therapies
Dr. Perez: I would like to divide systemic therapy into two subareas, the adjuvant setting and the metastatic setting.
For adjuvant therapy, we recommend systemic chemotherapy for patients based on all of these parameters that are mentioned. The duration of systemic therapy, the adjuvant setting, ranges from 2 months to 6 months depending on the tumor size and physician preferences. Many times we use targeted approaches, and they include anti-HER-2 therapy for patients with HER-2–positive breast cancer and anti-estrogen for patients with ER-positive breast cancer.
Standard duration of anti-HER–2 therapy is 1 year. The anti-HER–2 therapy is initiated concurrent with chemotherapy. When we use anti-estrogens for 5 years, they are typically initiated after the completion of chemotherapy.
A tremendous amount of research is being done trying to figure out the best chemotherapy drugs to use. There are ongoing trials trying to see if we can optimize the current outcome in the setting of anti-HER–2 therapies. The improvements in patient care have been dramatic by the introduction of these agents.
In the area of systemic therapy for metastatic disease, there now is clear understanding that there may be changes in the molecular profile or biochemical characteristics of breast cancer from initial diagnostic to the presence of metastatic disease that may occur in up to 25% of these cases. And it may be an issue of time. It may be an issue of impact of adjuvant therapy or molecular profiling at the time of metastatic disease. So it’s important that all practitioners consider obtaining a biopsy of the site when the patient presents with metastatic disease for the first time. First, to be sure that it is metastatic breast cancer and not another tumor, and, No. 2, to figure out whether these targets, ER, PR or HER-2, may be different from the primary to the metastatic sites, as they may guide therapy. This also provides the opportunity to collect tumors in the frozen state so we ultimately can do the type of diagnostic studies that will be the standard of care in the next 10 years, which will include gene sequencing of tumors for all of the patients diagnosed with breast cancer.
Survivorship
Dr. Perez: The focus is life after the diagnosis of breast cancer. So we are very interested in incorporating recommendations for optimal fitness, including regular exercise, as one of the ways to potentially decrease breast cancer recurrence and optimize survival, and also the importance of a well-balanced diet as part of survivorship. We recommend a well-balanced diet based on the recommendations of the FDA. We don’t recommend any specific vitamins or supplements. Maintaining calorie control and preventing significant weight gain may be particularly important in the setting of breast cancer survivorship.
Dr. Jacob: What about alcohol?
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Dr. Perez: We have a lot of epidemiological data demonstrating that regular alcohol use is associated with an increased risk of breast cancer development. The more people drink, the higher the incidence of breast cancer. In our clinic, we say try to be balanced. We don’t make recommendations that they should not drink alcohol, but we would not advocate daily alcohol use when we’re thinking about decreasing the risk of breast cancer.
Aromatase inhibitors
Dr. Perez: In the area of selection of adjuvant therapy or metastatic disease, aromatase inhibitors have been demonstrated to be a little bit better than tamoxifen for postmenopausal women. They have lower toxicity, and now that aromatase inhibitors have become generic compared with tamoxifen, there’s not that much cost differential. So most people prefer to use aromatase inhibitors vs. tamoxifen in postmenopausal women. In the premenopausal setting, tamoxifen is still the recommended drug. Studies are currently evaluating whether ovarian ablation should be recommended in addition to either tamoxifen or aromatase inhibitors in premenopausal women.
Dr. Jacob: Is there a difference between the two in terms of uterine cancer development?
Dr. Perez: Patients who have a history of breast cancer have a slightly increased risk of ovarian cancer but not an increased risk of uterine cancer. There is, however, a slightly increased risk of uterine cancer in postmenopausal women who receive tamoxifen.
Dr. Jacob: I’m talking about tamoxifen vs. aromatase inhibitors, with tamoxifen associated with increased uterine cancer.
Dr. Perez: The three side effects of tamoxifen that have led to increased use of aromatase inhibitors are thromboembolic events, hot flashes and the increased risk of endometrial cancer. Endometrial cancer is not seen as an increased risk of aromatase inhibitor, but on the other side, aromatase inhibitors can still cause some hot flashes. But then aromatase inhibitors have an increased risk of joint pain compared with tamoxifen. In terms of weighing the evidence of side effects, it is felt aromatase inhibitors are better than tamoxifen.
Dr. Jacob: What about mood disorders with either of these drugs?
Dr. Perez: One of the known side effects of tamoxifen is depression. It’s a very complicated situation in the setting of breast cancer because there are so many complications to having a diagnosis of breast cancer that might have an impact on the risk of depression. So this is a field that still deserves some more study.
Radiation exposure
Dr. Boxer: What are your recommendations for screening adolescent teenagers who receive mantle radiation?
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Dr. Perez: We have known certainly for a long time about this risk of radiation. Those patients are included in the guidelines of the American Cancer Society, as patients who have a greater than 20% risk of developing breast cancer, for screening to start at age 30 years. But right now, mammography is a very ineffective method to screen young women, especially in teenage years, because of the density of the breast.
Dr. Ghesani: There are actually two techniques, besides MRI, that can do that. One is called a gamma scintigraphy. It’s a dedicated detector that’s placed right over the breast with compression, just like a mammogram, but it’s used with the molecular marker that actually targets the mitochondria. They also have PEM scanners - positron emission mammography. It actually reconstructs the 3-D image. The idea is, the patients who are more likely to have early breast cancer are the ones who are subjected to this kind of technique.
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Dr. Perez: Those novel techniques have not received general approval because they’re only available at certain centers. We just got a PEM in Mayo in Jacksonville. In this field, one of the things that many people are concerned about is the amount of radiation to which we expose patients with these screening tests. And this is something that we get questions about on a daily basis. More education, related to the relative radiation exposure with different techniques, is going to be extremely important for educational purposes for physicians, all of the people doing research, and certainly from the patient’s standpoint.
Drugs in the pipeline
Dr. Jacob: For metastatic disease, which new agent is going to be the next one?
Dr. Perez: The HER-2 area is rich on investigational compounds that have a lot of promise. The two that have not been approved yet are pertuzmab - which is a HER-2, HER-3 dimer inhibitor — and TDM1, which is trastuzumab emtansine. That is the first drug antibody conjugate with activity in the setting of breast cancer. A randomized, phase 2 study showed improved response rate and PFS. Or we can cut the significant side effects in half by using TDM1 vs. traditional taxane in combination with trastuzumab. These are the two that have a potential for being approved in the next couple of years.
Dr. Vercellotti: The angiogenesis inhibitors are out?
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Dr. Perez: The way I view angiogenesis in the setting of breast cancer is that we all hoped that angiogenesis therapy was going to be the cure for cancer. And we have all learned, not only for breast cancer but for all tumor types, that these agents lead to improvements but the improvements are much more modest than we anticipated.
Dr. Ghesani: And so side effects are being reported at a higher frequency than before?
Dr. Perez: The side-effect situation is complicated because, the way some of the papers have been written, they’ve incorporated phase 1 trials and phase 2 trials. They’ve incorporated patients with renal cancer, colon cancer and breast cancer in some type of meta-analysis.
Dr. Jacob: Can you comment on BRCA mutations?
Dr. Perez: It is felt that about 5% to 10% of breast cancers occur due to inherited genetic mutations. And the two genes we can typically test for in clinical practice are BRCA1 or BRCA2, even though we clearly know there appear to be about eight genes that can be tested for on an investigational basis. There are guidelines that have been issued by many people related to who should have mutation testing.
In general, we divide breast cancer into three major groups: hormone-receptor positive, HER-2–positive and triple negative. We think there are at least seven to 14 types of breast cancer based on current gene profiling work, but for now, we have this triple-negative group, which encompasses patients whose tumors are ER-negative, PR-negative and HER-2–negative. We are in desperate need of a targeted drug for these patients, and that’s why we and others are conducting molecular work to identify those targets and then develop drugs.
For more information:
- Giuliano AE. JAMA. 2011;305:569-575.
- Hurvitz S. Abstract #5001. Presented at: European Society for Medical Oncology’s 36th Congress; Sept. 23-27, 2011; Stockholm.
- Whelan T. Presented at: 2011 ASCO Annual Meeting; June 3-7, 2011; Chicago.