Caroline Speers

Metastatic behavior of breast cancer subtypes.

PURPOSE Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected. METHODS Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression. RESULTS Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most common metastatic site in all subtypes except basal-like tumors. In multivariate analysis, compared with luminal A tumors, luminal/HER2 and HER2-enriched tumors were associated with a significantly higher rate of brain, liver, and lung metastases. Basal-like tumors had a higher rate of brain, lung, and distant nodal metastases but a significantly lower rate of liver and bone metastases. TN nonbasal tumors demonstrated a similar pattern but were not associated with fewer liver metastases. CONCLUSION Breast cancer subtypes are associated with distinct patterns of metastatic spread with notable differences in survival after relapse.

Population-Based Validation of the Prognostic Model ADJUVANT! for Early Breast Cancer

PURPOSE Adjuvant! (www.adjuvantonline.com) is a web-based tool that predicts 10-year breast cancer outcomes with and without adjuvant systemic therapy, but it has not been independently validated. METHODS Using the British Columbia Breast Cancer Outcomes Unit (BCOU) database, demographic, pathologic, staging, and treatment data on 4,083 women diagnosed between 1989 and 1993 in British Columbia with T1-2, N0-1, M0 breast cancer were abstracted and entered into Adjuvant! to calculate predicted 10-year overall survival (OS), breast cancer-specific survival (BCSS), and event-free survival (EFS) for each patient. Individual BCOU observed outcomes at 10 years were independently determined. Predicted and observed outcomes were compared. RESULTS Across all 4,083 patients, 10-year predicted and observed outcomes were within 1% for OS, BCSS, and EFS (all P > .05). Predicted and observed outcomes were within 2% for most demographic, pathologic, and treatment-defined subgroups. Adjuvant! overestimated OS, BCSS, and EFS in women younger than age 35 years (predicted-observed = 8.6%, 9.6%, and 13.6%, respectively; all P < .001) or with lymphatic or vascular invasion (LVI; predicted-observed = 3.6%, 3.8%, and 4.2%, respectively; all P < .05); these two prognostic factors were not automatically incorporated within the Adjuvant! algorithm. After adjusting for the distribution of LVI, using the prognostic factor impact calculator in Adjuvant!, 10-year predicted and observed outcomes were no longer significantly different. CONCLUSION Adjuvant! performed reliably. Patients younger than age 35 or with known additional adverse prognostic factors such as LVI require adjustment of risks to derive reliable predictions of prognosis without adjuvant systemic therapy and the absolute benefits of adjuvant systemic therapy.

The Impact of New Chemotherapeutic and Hormone Agents on Survival in a Population-based Cohort of Women with Metastatic Breast Cancer

Over the past decade, a number of new therapeutic agents have become available in the treatment of metastatic breast cancer (MBC). This study characterized the use and assessed the impact on survival of population‐based access to new agents for the treatment of MBC.

Impact on Survival of Time From Definitive Surgery to Initiation of Adjuvant Chemotherapy for Early-Stage Breast Cancer

PURPOSE To determine if time to start of adjuvant chemotherapy after curative surgery influences survival in early-stage breast cancer. PATIENTS AND METHODS A retrospective review was conducted of 2,594 patients receiving adjuvant chemotherapy for stage I and II breast cancer between 1989 and 1998 at the British Columbia Cancer Agency. Relapse-free survival (RFS) and overall survival (OS) were compared among patients grouped by time from definitive curative surgery to start of adjuvant chemotherapy (< or = 4 weeks, > 4 to 8 weeks, > 8 to 12 weeks, and >12 to 24 weeks). RESULTS RFS and OS were similar for women starting chemotherapy up to 12 weeks after surgery. OS hazard ratio (univariate) for initiation of chemotherapy more than 12 weeks compared with 12 weeks or less after surgery was 1.5 (95% CI, 1.07 to 2.10; P = .017). Five-year OS rates were 84%, 85%, 89%, and 78%, (log-rank P = .013); RFS rates were 74%, 79%, 82%, and 69% (log-rank P = .004) for patients starting chemotherapy 4 weeks or fewer, more than 4 to 8 weeks, more than 8 to 12 weeks, and more than 12 to 24 weeks after surgery, respectively. In multivariate analysis, independent prognostic factors were grade, size, nodal status, estrogen receptor, age, and lymphatic and/or vascular invasion. Initiation of adjuvant chemotherapy more than 12 weeks from surgery remained significantly associated with inferior survival, with a hazard ratio of 1.6 (95% CI, 1.2 to 2.3; P = .005). CONCLUSION This retrospective analysis suggests that adjuvant chemotherapy is equally effective up to 12 weeks after definitive surgery but that RFS and OS appear to be compromised by delays of more than 12 weeks after definitive surgery.

Human Epidermal Growth Factor Receptor 2 Overexpression As a Prognostic Factor in a Large Tissue Microarray Series of Node-Negative Breast Cancers

PURPOSE Human epidermal growth factor receptor 2 gene (HER2) is associated with a poorer outcome in node-positive breast cancer, but the results are conflicting in node-negative disease. This study assessed the prognostic impact of HER2 overexpression/amplification in a large series of node-negative breast cancers. PATIENTS AND METHODS A tissue microarray (TMA) series was constructed consisting of 4,444 invasive breast cancers diagnosed in British Columbia from 1986 to 1992. Within this series, 2,026 patients were node negative, of whom 70% did not receive adjuvant systemic therapy. The TMA series was assessed for estrogen receptor (ER) and HER2. Logistic regression modeling was used to estimate odds ratios at the 10-year follow-up. RESULTS HER2 was positive in 10.2% of the node-negative cohort. In this cohort, an inferior outcome was seen in patients with HER2-positive tumors compared with HER2-negative tumors for 10-year relapse-free survival (RFS; 65.9% v 75.5%, respectively; P = .01), distant RFS (71.2% v 81.8%, respectively; P = .004), and breast cancer-specific survival (BCSS; 75.5% v 86.3%, respectively; P = .001). A trend for a worse overall survival was also seen (P = .06). HER2 was an independent poor prognostic factor for RFS and BCSS at 10 years, with odds ratios of 1.71 (P = .01) and 2.03 (P = .003), respectively. The number of HER2-positive tumors that were <or= 1 cm was small, but there was a trend for a worse outcome in T1b tumors. CONCLUSION HER2 overexpression/amplification is correlated with a poorer outcome in node-negative breast cancer. Larger studies are needed to more clearly define the prognostic impact of HER2 in tumors <or= 1 cm, particularly within the separate hormone receptor subgroups.

Immunohistochemical Detection Using the New Rabbit Monoclonal Antibody SP1 of Estrogen Receptor in Breast Cancer Is Superior to Mouse Monoclonal Antibody 1D5 in Predicting Survival

PURPOSE Estrogen receptor (ER) expression predicts improved breast cancer-specific survival and reduced risk of recurrence and is targeted in breast cancer therapy. A high-quality antibody to identify ER-positive patients plays an important role in clinical decision making for women with breast cancer. This study evaluates immunohistochemistry using two anti-ER antibodies, a new rabbit monoclonal antibody (SP1) and the mouse monoclonal antibody (1D5), in relation to biochemical ER assay results and clinical data on survival and adjuvant systemic therapy. PATIENTS AND METHODS A population-based tissue microarray series of 4,150 invasive breast cancers was constructed. All patients had staging, pathology, treatment, and follow-up information. The median follow-up was 12.4 years and the median age at diagnosis 60 years. Survival analysis and log-rank tests were used to evaluate the prognostic value of ER status and correlations with clinical data. RESULTS Among the 4,105 samples interpretable for both antibodies, SP1 detected ER positivity in 69.5% and 1D5 in 63.1% of cases. Both monoclonal antibodies are demonstrated to be good prognostic indictors for breast cancer-specific and relapse-free survival. In multivariate analysis, including age, tumor size, grade, and lymphovascular and nodal status, SP1 was a better independent prognostic factor than 1D5. Among patients with discrepant ER results, the 8% of patients who were SP1 positive/1D5 negative showed good outcomes, and the 2% SP1-negative/1D5 positive had poor outcomes. Maintaining the same 92% specificity and 98% positive predictive value, SP1 is 8% more sensitive than 1D5 using biochemical assay as gold standard. CONCLUSION SP1 represents an improved standard for ER immunohistochemistry assessment in breast cancer.

Ten-Year Outcomes in a Population-Based Cohort of Node-Negative, Lymphatic, and Vascular Invasion–Negative Early Breast Cancers Without Adjuvant Systemic Therapies

PURPOSE To discuss the absolute benefits from adjuvant systemic therapy knowledge of long-term outcomes and baseline risks of relapse and disease-specific survival are required. We assessed the 10-year outcomes in a population-based cohort of node-negative (N-) lymphovascular negative (LV-) early breast cancers diagnosed from 1989 to 1991 who did not receive adjuvant systemic therapy. METHODS One thousand one hundred eighty-seven cases of pT(1-2)N(0) LV- breast cancers with a median follow-up of 10.4 years were reviewed. Kaplan-Meier survival curves for relapse free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS) were compared with log-rank tests with cohorts stratified for tumor size and grade. RESULTS The median age of this series was 62 years. Four hundred thirty tumors were < or = 1 cm in diameter (cohort 1), 507 were 1.1-2 cm (cohort 2), and 250 were 2.1 to 5 cm in diameter (cohort 3). The 10-year outcomes for cohorts 1, 2, and 3, respectively, were significantly different: RFS, 82%, 75%, and 66%; BCSS, 92%, 90%, and 77%; and OS, 79%, 78%, and 66%. Tumor grade significantly altered outcome within size cohorts, particularly in pT(1)N(0) breast cancers. CONCLUSION This study provides detailed information on the continued relapse and breast cancer death rate to 10 years of follow-up. Specifically, without adjuvant systemic therapy, patients with LV-, N - breast cancer had a > or = 25% 10-year risk of relapse and a corresponding 10-year breast cancer death rate of > or = 10% if they had either a grade 3 tumor < or = 1 cm, a grade 2 to 3 tumor from 1.1 to 2 cm, or any grade tumor greater than 2 cm.

Prognostic Significance of the Number of Axillary Lymph Nodes Removed in Patients With Node-Negative Breast Cancer

PURPOSE The objective of the study was to evaluate the association between the number of lymph nodes removed at axillary dissection and recurrence and survival for patients with node-negative invasive breast cancer. PATIENTS AND METHODS Subjects were 2,278 women with pathologically node-negative invasive breast cancer, diagnosed from 1989 to 1993 in British Columbia, Canada. Women aged > or = 90 years, with pure in-situ, bilateral invasive breast cancer or T4, N1, N2, or M1 stage, or who had axillary radiation were excluded. Two groups were defined for analysis: node-negative with no systemic therapy (n = 1,468) and node-negative with systemic therapy (n = 810). Median follow-up was 7.5 years. Prognostic variables assessed were age at diagnosis, tumor size, tumor grade, invasion of lymphatics, veins, or nerves, estrogen receptor status, and number of nodes removed. RESULTS For patients not receiving systemic therapy, regional relapse was significantly increased with smaller numbers of nodes removed (P =.03). There was a trend toward shorter overall survival with fewer nodes removed (P =.06). Node-negative patients who received systemic therapy did not have a higher regional relapse rate or shorter overall survival when fewer nodes were recovered. CONCLUSION Recovery of a small number of negative lymph nodes at axillary dissection likely understages patients and leads to undertreatment, resulting in an increased regional relapse rate and poorer survival. The use of systemic therapy may overcome this effect. The number of nodes removed, in conjunction with other prognostic factors, may be useful in selecting node-negative patients for systemic therapy.

Evolving Treatment Strategies for Inflammatory Breast Cancer: A Population-Based Survival Analysis

PURPOSE To determine if mastectomy (Mx) use, chemotherapy (CT) intensity, or treatment sequence of CT, radiation therapy (RT), and Mx have improved outcome for inflammatory breast cancer (IBC). PATIENTS AND METHODS A retrospective analysis of 485 patients with IBC diagnosed in British Columbia between 1980 and 2000 analyzed locoregional relapse-free survival (LRFS) and breast cancer-specific survival (BCSS) by treatment intent and treatment received. Curative intent was defined as delivery of more than four cycles of anthracycline-based CT plus locoregional RT in patients without distant metastases. RESULTS Median follow-up among survivors was 6.5 years. Median BCSS was 1.0 and 3.2 years for patients with distant metastases at diagnosis or those who were curatively treated, respectively. Among patients treated curatively (n = 308), there were no significant differences in LRFS or BCSS with timing of Mx before or after CT/RT, time between diagnosis and RT, or the sequence of RT and CT. Patients receiving more intensive CT had improved 10-year BCSS compared with standard CT (43.7% v 26.3%; P = .04). Ten-year LRFS for patients having Mx after CT, Mx before CT, and without Mx was 62.8%, 58.6%, and 34.4%, respectively (P = .0001); the corresponding 10-year BCSS was 36.9%, 19.9%, and 22.5%, respectively (P = .005). On multivariate analysis, Mx was associated with improved LRFS (P = .04). Independent prognostic factors for BCSS were menopausal status (P = .02), estrogen receptor status (P = .02), and CT type (P = .05). CONCLUSION This retrospective analysis suggested that mastectomy, in conjunction with CT and RT, seemed to enhance locoregional control, whereas modern CT regimens seemed to improve BCSS.

Patients With T1 to T2 Breast Cancer With One to Three Positive Nodes Have Higher Local and Regional Recurrence Risks Compared With Node-Negative Patients After Breast-Conserving Surgery and Whole-Breast Radiotherapy

PURPOSE To evaluate locoregional recurrence according to nodal status in women with T1 to T2 breast cancer and zero to three positive nodes (0-3N+) treated with breast-conserving surgery (BCS). METHODS AND MATERIALS The study subjects comprised 5,688 women referred to the British Columbia Cancer Agency between 1989 and 1999 with pT1 to T2, 0-3N+, M0 breast cancer, who underwent breast-conserving surgery with clear margins and radiotherapy (RT) of the whole breast. The 10-year Kaplan-Meier local, regional, and locoregional recurrence (LR, RR, and LRR, respectively) were compared between the N0 (n = 4,433) and 1-3N+ (n = 1,255) cohorts. The LRR was also examined in patients with one to three positive nodes (1-3N+) treated with and without nodal RT. Multivariate analysis was performed using Cox regression modeling. RESULTS Median follow-up was 8.6 years. Systemic therapy was used in 97% of 1-3N+ and 41% of N0 patients. Nodal RT was used in 35% of 1-3N+ patients. The 10-year recurrence rates in N0 and 1-3N+ cohorts were as follows: LR 5.1% vs. 5.8% (p = 0.04); RR 2.3% vs. 6.1% (p < 0.001), and LRR 6.7% vs. 10.1% (p < 0.001). Among 817 1-3N+ patients treated without nodal RT, 10-year LRR were 13.8% with age <50 years, 20.3% with Grade III, and 23.4% with estrogen receptor (ER)-negative disease. On multivariate analysis, 1-3N+ status was associated with significantly higher LRR (hazard ratio [HR], 1.85; 95% confidence interval, 1.34-2.55, p < 0.001), whereas nodal RT significantly reduced LRR (HR, 0.59; 95% confidence interval, 0.38-0.92, p = 0.02). CONCLUSION Patients with 1-3N+ and young age, Grade III, or ER-negative disease have high LRR risks approximating 15% to 20% despite BCS, whole-breast RT and systemic therapy. These patients may benefit with more comprehensive RT volume encompassing the regional nodes.