Breast Cancer BREAST CANCER
Local Recurrence Risk Greater with Lumpectomy Versus Mastectomy in Women with BRCA Mutations CHICAGO—Women with early-stage breast cancer and the BRCA 1 or 2 mutations who underwent breast-conserving therapy (BCT) (ie, surgery and radiotherapy; n = 160) had more local recurrences compared with women who received mastectomy with or without postmastectomy radiotherapy (MX; n = 213). A local event was a recurrence of the initial breast cancer in the chest wall or a new contralateral breast cancer. In this retrospective, multicenter analysis performed by chart review of 373 women with invasive, nonmetastatic breast cancer, local failure as a component of first failure was greater for the BCT group than the MX group (P = .0043). The few patients with both BRCA 1 and 2 mutations were excluded from the analysis. The mean follow-up for both cohorts was 10 years. Lead investigator Lori Pierce, MD, professor of radiology at the University of Michigan in Ann Arbor, said the rates of distant failure, breast cancer-specific survival (Table), and overall survival were similar between the groups (P = .29, P = .85, P = .55, respectively). She presented her results at the 44th Annual Meeting of the American Society of Clinical Oncology in Chicago in June. The only predictors of local failure were a lack of use of adjuvant chemotherapy for BCT patients (hazard ratio [HR] = 3.4; P = .0095) or the presence of lobular histology for MX patients (HR = 15.0; P = .0009).
Radiation effects Since radiation damages DNA and the BRCA genes are active in DNA repair, the investigators were interested in the occurrence of contralateral
Table. Breast Cancer–specific Survival 5-year (%)
10-year (%)
15-year (%)
BCT
95.1
92.5
90.8
MX
94.9
91.6
90.4
BCT indicates breast-conserving therapy; MX, mastectomy with or without postmastectomy radiotherapy.
Photo courtesy of ASCO
breast cancers (CBCs) from radiation scatter. “It’s a very limited area in the medial aspect of the contralateral breast, but you can still see very, very low rates of scatter even with current techniques of radiation,” Pierce noted. At 15 years of follow-up, they found equivalent rates of CBCs for the BCT and for the MX groups with or without radiotherapy (P = .77). Also for the MX cohort, the rate of CBCs was independent of the use of radiotherapy (P = .60). The investigators concluded that radiation scatter did not increase the rate of CBC. The study findings may be useful when discussing treatment options with patients. “I think this adds to the information that we have to be able to counsel women who are BRCA 1 and 2 carriers who have early-stage breast cancer,” Pierce said. “Some patients are highly desirous of breast conservation, and this study doesn’t mean that they cannot do breast conservation. It just gives us an idea of the outcomes both locally and, more importantly, systemically.” She noted that her study did not include enough events to draw any conclusions about the effects of oopherectomy or hormonal therapy, but findings from other series suggest that these interventions can reduce both ipsilateral and contralateral breast events. “In a full discussion of the BRCA 1 and 2 carriers, which is a long and very complicated discussion, oopherectomy and tamoxifen are both important to bring into the discussion,” she advised. —DMK
All-oral Therapy of HER2-positive Breast Cancer a Possibility
BREAST CANCER
CHICAGO—At the 2008 annual meeting of the American Society of Clinical Oncology in Chicago in June, Dennis Slamon, MD, PhD, of the University of California at Los Angeles, stimulated vigorous discussion with his presentation of a study of a new oral drug combination for HER2-positive breast cancer. The comDennis Slamon, MD, PhD bination incorporated lapatinib and pazopanib, a development-stage inhibitor of multiple tyrosine kinases, including the one associated with the receptor for vascular endothelial growth factor (VEGF). Controversy centered on the validity of Slamon’s findings, garnering reactions from mild praise to outright ridicule. Focusing on methodological problems of the research, critics said the study was underpowered, of too short duration, and had many incomplete data sets. Others felt it was promising as a preliminary study and showed that a combination of smallmolecule VEGF and HER2 inhibitors could have activity in this disease. This 12-week study was a randomized trial of pazopanib plus lapatinib (PL) versus lapatinib alone in patients with advanced or metastatic HER2-positive breast cancer to examine the safety 28
and efficacy of so-called “dual pathway inhibition” using these oral agents. Lapatinib is an inhibitor of the tyrosine kinase of the HER2 receptor. Patients had received no prior chemotherapy or HER2directed therapy for their advanced disease. Twelve-week efficacy data were available for 69% of the pazopanib-lapatinib and 77% of the lapatinib patients. Progressive disease, the primary end point, occurred in 19% of the PL group and in 27% of the lapatinib group. The response rate was 44% for PL and 30% for lapatinib. Target lesions were reduced in 73% versus 43% of patients, respectively. The incidences of diarrhea, rash, and nausea were similar in the two arms. However, aspartate aminotransferase and bilirubin increases were about twice as common in the PL arm. “The major conclusion is that the combination of pazopanib and lapatinib is better than lapatinib alone in HER2-positive breast cancer,” Slamon said. Responding to criticisms that 37 of the 141 patient data sets were missing because of problems at some of the international trial sites, he explained that missing data were classified as progressive disease. And since more were missing for the PL group, if anything the study was biased against the combination. “And yet the combination looks better,” he said. Harold Burstein, MD, PhD, of the Dana-Farber Cancer Institute in Boston, commented, “In the very preliminary incomplete data, they showed it did sug-
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gest that you increase the response rate and possibly the time to progression by using inhibition of both pathways.” He recommended a definitive study to follow up on this “biologically interesting idea.” In terms of dual-pathway inhibition, Mark Pegram, MD, of the Braman Family Breast Cancer Institute at the University of Miami in Florida, said, “The nice feature of the [PL] strategy is that it’s an all-oral regimen, whereas trastuzumab and bevacizumab is an all-[intravenous] regimen. So in terms of practicality and patient convenience, it might be an interesting option. —DMK
Did you
Know?
Americans made more than 1 billion physician or hospital outpatient or emergency department visits in 2006; 70% received at least one prescription, most often an analgesic. Source: www.CDC.gov. 8/6/08.
September 2008