Craig D. Shriver

BACKGROUND: Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. METHODS: We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. "Hot spots" representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. RESULTS: The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status of the axillary nodes was 97 percent (392 of 405); the specificity of the method was 100 percent, the positive predictive value was 100 percent, the negative predictive value was 96 percent (291 of 304), and the sensitivity was 89 percent (101 of 114). The sentinel nodes were outside the axilla in 8 percent of cases and outside of level 1 nodes in 11 percent of cases. Three percent of positive sentinel nodes were in nonaxillary locations. CONCLUSIONS: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient.

Importance: African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities. Objectives: To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes. Design, Setting, and Participants: Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas. Main Outcomes and Measures: Breast cancer–free interval, tumor molecular features, and genetic variants. Results: Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11). Conclusions and Relevance: On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.

PURPOSE: E75 is an immunogenic peptide from the HER2/neu protein that is highly expressed in breast cancer. We are conducting a clinical trial of an E75 + granulocyte-macrophage colony-stimulating factor vaccine to assess safety, immunologic response, and the prevention of clinical recurrences in patients with disease-free, node-positive breast cancer (NPBC). PATIENTS AND METHODS: Fifty-three patients with NPBC were enrolled and HLA typed. HLA-A2+ patients (n = 24) were vaccinated, and HLA-A2- patients (n = 29) are observed prospectively as clinical controls. Local/systemic toxicities, immunologic responses, and time to recurrence are being measured. RESULTS: Only minor toxicities have occurred (one grade 3 [4%]). All patients have demonstrated clonal expansion of E75-specific CD8+T cells that lysed HER2/neu-expressing tumor cells. An optimal dosage and schedule have been established. Patients have developed delayed-type hypersensitivity reactions to E75 postvaccination compared with controls (33 v 7 mm; P < .01). HLA-A2+ patients have been found to have larger, more poorly differentiated, and more hormonally insensitive tumors compared to HLA-A2- patients. Despite this, the only two deaths have occurred in the control group. The disease-free survival in the vaccinated group is 85.7% compared to 59.8% in the controls at 22 months' median follow-up with a recurrence rate of 8% compared to 21%, respectively (P < .19). Median time to recurrence in the vaccinated patients was prolonged (11 v 8 months), and recurrence correlated with a weak delayed-type hypersensitivity response. CONCLUSION: This HER2/neu (E75) vaccine is safe and effective in eliciting a peptide-specific immune response in vivo. Induced HER2/neu immunity seems to reduce the recurrence rate in patients with NPBC.

The identification of extensive genetic heterogeneity in human breast carcinomas poses a significant challenge for designing effective treatment regimens. Significant genomic evolution often occurs during breast cancer progression, creating variability within primary tumors as well as between the primary carcinoma and metastases. Current risk allocations and treatment recommendations for breast cancer patients are based largely on characteristics of the primary tumor; however, genetic differences between disseminated tumor cells and the primary carcinoma may negatively impact treatment efficacy and survival. In this review we (1) present current information about genomic variability within primary breast carcinomas, between primary tumors and regional/distant metastases, among circulating tumor cells (CTCs) and disseminated tumor cells (DTCs), and in cell-free nucleic acids in circulation, and (2) describe how this heterogeneity affects clinical care and outcomes such as recurrence and therapeutic resistance. Understanding the evolution and functional significance of the composite breast cancer genome within each patient is critical for developing effective therapies that can overcome obstacles presented by molecular heterogeneity.