OncoLink Professor On-Call: Lawrence Solin, MD provides exclusive expert review and insights from the recent San Antonio Breast Cancer Symposia for OncoLink
The 29th Annual San Antonio Breast Cancer Symposium was held from Thursday, December 14 through Sunday, December 17, 2006. A wide range of topics was discussed. This symposium is widely considered to be one of the major breast cancer conferences in the world. As such, much of the scientific information presented at this symposium is quickly integrated into contemporary breast cancer practice.
Epidemiology and Prevention
Dr. Peter Ravdin presented data from SEER (Surveillance, Epidemiology, and End Results) that showed a dramatic and statistically significant decrease in the incidence of breast cancer in the United States between 1998 and 2003. The absolute decrease in the number of new breast cancer cases was about 14,000 in 2003. Given that the SEER data represent a cross-section of the United States, these results are an important public health finding. The authors hypothesized that the decline in the widespread use of hormone replacement therapy (HRT) may account for these findings. If correct, these results could have large-scale public health implications, and suggest that public health measures can have a dramatic and meaningful impact on overall health relative to a specific disease outcome.
The WINS (Women's Intervention Nutrition Study) randomized 2,437 patients to reduced fat intake compared to control. In addition to reduced fat intake, mean body weight was also significantly lower in the intervention group (p = .005). The hazard ratio for the intervention group was .76 for breast cancer events. These results suggest that dietary interventions can significantly reduce the risk of breast cancer, which of course has enormous public health implications. Subset analysis suggested that the effect was mainly for the patients with hormone receptor negative tumors, a group for which hormone treatments are ineffective. The mechanism of the improved outcome is unclear, but is hypothesized to occur through nonhormonal pathways. The improvement in outcome for the intervention group might relate to the reduction in dietary fat intake, lower body weight, or both. First results from this study are scheduled for publication shortly (Chlebowski R, JNCI, in press).
Updated results were presented from the NSABP (National Surgical Adjuvant Breast and Bowel Project) STAR (study of tamoxifen and raloxifene) P-2 trial. In this study, 19,747 postmenopausal women at increased risk for developing breast cancer were randomized to receive 5 years of tamoxifen vs. raloxifene. In a prior report, no differences were reported between the two groups for the development of invasive breast carcinoma, although tamoxifen was reported to have a lower rate of development of non-invasive breast carcinoma. The toxicity profiles for the two agents were both acceptably low, but slightly different. In the updated results, the tamoxifen arm continues have lower rates of developing DCIS (risk ratio = 1.46), LCIS (risk ratio = 1.37), and all non-invasive events (risk ratio = 1.40). The mechanism for this differential effect remains uncertain, but suggests that the mechanism by which chemoprevention works is complex.
In clinical practice, these updated results confirm the initial findings of a differential effect between tamoxifen and raloxifene, and suggest that while either agent is effective for the primary endpoint of reduction for invasive carcinoma, the choice of agent for the individual patient might be influenced by the subtle differences in the toxicity profile. Further, if an individual patient does not tolerate one of the two agents, changing to the other can be considered.
In a discussion of breast cancer prevention, Dr. Leslie Ford from the National Cancer Institute suggested guidelines for selecting a chemoprevention agent. For the premenopausal woman, tamoxifen is the only agent with demonstrated effectiveness. In the postmenopausal setting, raloxifene is preferred for the woman with a uterus (because of the lower risk of endometrial cancer associated with raloxifene compared to tamoxifen), and either tamoxifen or raloxifene can be considered for the woman without a uterus. Future trials will evaluate the potential efficacy of an aromatase inhibitor for prevention in the postmenopausal woman.
Early Stage Disease: Local-Regional Treatment
The first report from the ECOG (Eastern Cooperative Oncology Group) E5194 study was presented. In this study, carefully selected patients with low risk DCIS were prospectively identified for treatment with excision alone, without breast radiation. Adjuvant tamoxifen was optional. Low risk patients in this study were defined as: (a) low-intermediate grade plus size < 2.5 cm or high grade plus size < 1.0 cm; (b) excision of the primary DCIS lesion; (c) pathologically confirmed negative margins with a minimum negative margin width of 3 mm or no tumor in a re-excision specimen; and (d) post biopsy mammogram with no residual microcalcifications for those lesions presenting initially with microcalcifications on mammography. All specimens underwent rigorous pathologic evaluation with serial sectioning.
The results from this study demonstrated a relatively low risk of local recurrence of 6.8% at 5 years for the low-intermediate DCIS subset. However, the risk of local recurrence was 13.7% at 5 years for the high grade subset.
The importance of this study is that it is one of the first large studies to attempt to identify prospectively patients who can be treated with omission of radiation, albeit with careful patient selection and rigorous evaluation of the pathologic specimen. Before these results are implemented in routine clinical practice, caveats regarding the interpretation of this data include the relatively short follow-up (median 5 years) and limited information about clinically important subsets (e.g., use of tamoxifen, patient age, minimum negative margin width). In clinical practice, these results demonstrate that high grade lesions cannot adequately be treated with excision alone, and that radiation should be included as a component of management. Relative to low-intermediate grade lesions, the outcomes will need to be strengthened with longer follow-up, and subset information will be useful to better tailor treatment for these lesions.
Dr. Harry Bartelink presented an update of the EORTC (European Organization for Research and Treatment of Cancer) trial 22881-10882. After breast conserving surgery, pathologically confirmed negative margins, and whole breast radiation of 50 Gy, patients in this study were randomized to receive an additional 16 Gy radiation boost to the primary tumor site compared to no boost. The results showed an improvement in local recurrence for the overall group with an absolute benefit of 4.0% at 10 years (6.2% vs. 10.2%; p < .0001). Further, all age subsets showed an improvement in local recurrence ranging from an absolute benefit of 10.4% at 10 years for patients age < 40 years (p = .0014) to 3.5% for patients age > 60 years (p .0008). There were fewer distant failures in the radiation boost group (305 vs. 353, respectively), but this has not yet translated into a difference in survival at 10 years (82% in both groups; p = .93). The use of a radiation boost was associated with a slightly increased risk of fibrosis of 2.8% (p < .0001).
In clinical practice, this EORTC study strongly suggests that all breast conservation patients, regardless of age, should receive a radiation boost to the primary tumor site after conventional whole breast radiation. Most radiation oncologists routinely add a boost after whole breast radiation. Although the early results from this study were not as strongly in favor of the boost for the older age group, the updated results from this study indicate that all patients benefit from the addition of the radiation boost. The boost treatment resulted in a small, but acceptably, increased rate of fibrosis after treatment. Although this trial showed a dose response effect in favor of higher radiation doses, it is unlikely that even higher radiation doses (beyond 65-66 Gy) will be tested in randomized trials because of the known risks of substantially increased complications with these higher doses, as well as the excellent local control rates seen with conventional radiation doses. On balance, total radiation doses in the range of 60-66 Gy appear to be the optimal range for breast conservation treatment to balance the high rate of local control with a low risk of complications.
The optimal management of older women continues to be actively investigated. In a randomized trial, 636 women with estrogen receptor positive, T1 tumors received lumpectomy and tamoxifen, and were then randomly assigned to radiation vs. no radiation. With a median follow-up of 7.9 years, the absolute benefit for local-regional recurrence was about 6% better for the radiation arm (7% vs.1%; p = .0001), and improvements in both local control and regional control were demonstrated. This study demonstrated its primary endpoint of an improvement in local control associated with radiation treatment. The study was not sufficiently powered to detect differences in survival or distant metastases, and the results of these endpoints of study are accordingly not different.
The clinical importance of this study must be put into the context of the performance status of the individual patient. An otherwise healthy 70-year old woman has an estimated life expectancy of approximately 19 years, and an otherwise healthy 80-year old woman has an estimated life expectancy of approximately 9 years. In the older age category, breast cancer treatment should consider the disease in the context of the patient. For example, a healthy 70-year old woman without significant co-morbidities deserves maximally aggressive treatment (including surgery, adjuvant systemic treatment, and conventional radiation), whereas an 85-year old woman with substantial co-morbidities might reasonably be treated with a less aggressive program (e.g., lumpectomy plus adjuvant hormonal therapy).
Dr. Bruno Cutuli presented intriguing data on a retrospective cohort of 325 patients with LCIS (lobular carcinoma in situ) of the breast. The majority (77%) of the patients underwent “conservative surgery,” although the meaning of this term is uncertain in the context of LCIS. After conservative surgery, the 10-year rate of local recurrence was 23%, of which 55% were invasive. The 10-year rate of contralateral breast cancer was 7.8%, of which 70% were invasive. Radiation after conservative surgery was associated with a decrease in local recurrence compared to no radiation (5.4% vs. 19.2%, respectively). Given the ipsilateral and contralateral risks associated with LCIS, the clinical importance of this diagnosis is to identify these patients with LCIS as high risk and potential candidates for prevention strategies. While prophylactic mastectomy is curative, prevention strategies are typically chosen by patients in lieu of more radical surgery.
Early Stage Disease: Adjuvant Systemic Treatment
Dr. Terry Mamounas presented data on the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-33 trial, in which patients were randomized after 5 years of adjuvant tamoxifen to receive 5 years of exemestane vs. placebo. Because of the results published in 2003 from the NCIC (National Cancer Institute of Canada) MA-17 study showing a benefit to adding an aromatase inhibitor after 5 years of tamoxifen (P. Goss, NEJM, 2003), patients in the NSABP trial on the placebo arm were offered the opportunity to cross over to adjuvant exemestane. At the time of unblinding of the two arms of the NSABP trial, 44% (344/779) of the patients on the placebo arm crossed over to take exemestane, whereas 72% (560/783) of the patients continued on the exemestane arm. Despite the confounding effect from the crossover, especially for those patients originally on the placebo arm, there was an improvement in relapse free survival in the exemestane arm (relative risk = .50; p = .03), and a borderline improvement in disease free survival (relative risk = .68; p = .07), but no difference in overall survival (relative risk = 1.2; p = .63).
The importance of these data is to confirm and solidify the data supporting the use of an aromatase inhibitor (AI) for the hormone receptor positive, post menopausal patient. In clinical practice, many such patients have been taking tamoxifen for up to 5 years as adjuvant therapy, as has been the standard practice. The NSABP study reaffirms the importance of adding an aromatase inhibitor after 5 years of adjuvant tamoxifen. However, the cross over of patients from the placebo arm to the aromatase inhibitor treatment raises potential problems in the interpretation of the data from the NSABP study and the NCIC study. In both trials, there may be no ability to demonstrate any overall survival benefit with the addition of an AI because of cross over, and the magnitude of the benefit from adding an AI may be difficult to estimate.
Ten-year results were presented from the Austrian Breast Cancer Study Group ABCSG-05 study that randomized premenopausal patients to adjuvant CMF vs. goserelin plus tamoxifen. In the subset of patients receiving CMF, 62.8% of the patients became amenorrheic after chemotherapy. The development of amenorrhea after chemotherapy was strongly prognostic for overall survival (hazard ratio = .569; p = .0042) and relapse free survival (hazard ratio = .656; p = .0093). However, the benefit of amenorrhea after chemotherapy was not significant in the subgroup of patients with low hormone receptor expression or Her2 overexpression.
The clinical importance of these findings is to support the recent interest in and development of clinical trials for ovarian suppression in the premenopausal patient. Randomized trials of oophorectomy as adjuvant treatment for breast cancer in the premenopausal patient have a long history, but even in the modern era, the optimal use of ovarian suppression remains uncertain. The ABCSG study bolsters the rationale for the current trials of ovarian suppression. In addition, the reported results suggest subgroups of patients (high hormone receptor expression or negative Her2) that might optimally be targeted for ovarian suppression in clinical practice.
Some of the most interesting presentations at the symposium related to various works in progress, and the possibility of exciting future directions in breast cancer prevention and treatment. While none are yet ready for implementation in clinical practice, many new avenues for prevention, research, and treatment were presented.
One of the major themes of the symposium is that breast cancer is a heterogeneous disease. As a consequence, future directions in breast cancer treatment will become increasingly tailored to specific subsets of patients. Specifically targeted therapies have already taken a major place in the clinical management of breast cancer patients (e.g., based on hormone receptor status and Her2 status), and this trend will undoubtedly become more sophisticated in the future.
Intriguing data was presented on a Her2 vaccine. In this study, 90 patients received the vaccine, and 81 patients were observed. Although with small numbers of patients and a short median follow-up of 2 years, the recurrence rate was 5.6% (5/90) with the vaccine compared to 14.8% (12/81) without the vaccine (p = .04). These results raise the possibility of using a vaccine in both the adjuvant setting and the prevention setting. While vaccines are a long way from implementation in clinical practice until much more clinical trial data have been obtained, vaccines represent a potentially new line of clinical agents that might one day prove valuable.
In a thought-provoking study, Dr. James Holland presented data that a substantial fraction of human breast cancers may have a viral etiology. Supporting this contention was the finding that about 38% of human breast cancers have evidence of DNA similar to MMTV (mouse mammary tumor virus), and that the incidence of breast cancer is related to the species of mouse that carries MMTV. While certainly provocative, if confirmed, these data suggest a number of potentially interesting avenues for prevention and treatment.
The role of tumor-host interaction was reviewed. Host-tumor interactions remain another potential avenue for innovative research. For example, one clinical observation is that most, but not all, patients with the BRCA gene mutation develop breast cancer. Host-tumor interactions may explain some of these observed clinical phenomena, and may provide the potential for new therapeutic targets.
A number of presentations addressed the role of angiogenesis and breast cancer. For tumors to grow, new blood vessels need to be generated to sustain growth. In one of the first randomized trials to demonstrate the effect of an anti-angiogenic drug (bevicizumab), patients with metastatic breast cancer were randomized to chemotherapy with vs. without bevicizumab, and a substantial improvement in relapse free survival was seen with the combination (p < .001). This success has led to the development of randomized trials in the adjuvant setting comparing standard chemotherapy with vs. without bevicizumab.