Judy-Anne W. Chapman

Clinical behavior of untreated axillary nodes after local treatment for primary breast cancer

AbstractBackground: The purpose of this study was to examine the rate of axillary failure in patients with primary breast cancer treated without axillary dissection or radiation and to determine what factors may be associated with axillary failure. Methods: We studied 112 patients with invasive breast cancer treated for primary disease with breast-conserving surgery without axillary dissection or radiation to the breast or axilla, accrued between 1977 and 1986. Data for these patients were prospectively gathered for a research database and reviewed retrospectively to determine axillary failure. The effects of age, tumor size, estrogen receptor (ER) status, progesterone receptor (PgR) status, histologic grade, nuclear grade, and tumor emboli on time to axillary failure were examined. Results: The median follow-up was 9.6 years. There were 26 axillary recurrences, resulting in a 10-year actuarial nodal control rate of 72%. Patients with nodal failure proceeded to axillary dissection with minimal morbidity. In both univariate and multivariate analyses, only tumor size was significantly associated with axillary failure (p=0.04 andp=0.06, respectively). Conclusions: This study demonstrates a significant effect of tumor size on axillary failure and a reasonable rate of local control in small tumors. Further research should examine the utility of axillary dissection in women with small breast cancers.

Open-label phase III randomized controlled trial comparing taxane-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women with HER2+ metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919.

LBA671 Background: The relative efficacy of L vs T when combined with Tax chemotherapy in the first-line setting of metastatic breast cancer (BC) is unknown. METHODS MA.31 compares Tax-based therapy, paclitaxel 80mg/m2 wkly or docetaxel 75mg/m2 3 wkly for 24 wks in combination with L or T. The L dose was 1,250 mg po daily with Tax followed by 1,500 mg daily (LTax/L). After a loading dose, the T dose was 2 mg/kg wkly or 6 mg/kg 3 wkly + Tax followed by T 6 mg/kg 3 wkly (TTax/T). Stratification was by prior neo/adjuvant HER2 therapy, prior neo/adjuvant Tax, planned Tax (paclitaxel vs docetaxel), and liver metastases. The primary endpoint is ITT progression-free survival (PFS), defined as time from randomization to objective progressive disease based on RECIST criteria or death from any cause. The protocol-specified IA was performed after observing 333 PFS events; the trial was to stop if the 2-sided p-value from the stratified log-rank test was less than 0.03. The NCIC CTGs independent DSMC reviewed IA results and recommended disclosure because the superiority boundary was crossed. A secondary analysis utilized central laboratory-confirmed HER2 + status. RESULTS Between July 17 2008 and Dec 1 2011, 652 pts were accrued. Data from 636 pts (525 HER2 centrally confirmed) were included in the IA with clinical cutoff date of Nov 7 2011 and database lock of Apr 13 2012. Median follow-up was 13.6 mos, 12.9 mos for LTax/L pts and 14.0 mos for TTax/T patients. In the ITT analysis, PFS was inferior with LTax/L compared to TTax/T hazard ratio (HR) =1.33; 95% CI 1.06-1.67; p=0.01. LTax/L had median PFS 8.8 mos (95% CI 8.3-10.6) compared to TTax/T 11.4 mos (95% CI 10.8-13.7). PFS in the centrally confirmed HER2+ had HR 1.48 (95%CI 1.15-1.92; p=0.003) (LTax/L to TTax/T). No difference in overall survival was detected (LTax/L to TTax/T) HR= 1.1 (95% CI 0.75-1.61; p=0.62). More grade 3-4 diarrhea and rash was observed with LTax/L (p<0.001). CONCLUSIONS LTax/L therapy is associated with a shorter PFS compared to TTax/T as first line therapy for HER2+ metastatic BC. ClinicalTrials.gov: NCT00667251. CCSRI grant: 021039. Supported by GlaxoSmithKline.

Competing causes of death for primary breast cancer

AbstractBackground: A patients likelihood of dying from breast cancer or another cause can be assessed with competing risks analyses. Methods: Data for a cohort of 678 patients with primary invasive breast cancer accrued from 1971 to 1990, updated to 1995, included cause of death (e.g., breast cancer vs. other cause). We investigated the effects of age, tumor size, nodal status, ER, PgR, and adjuvant therapy (hormones, chemotherapy, radiotherapy) on type of death and time to death for patients of all ages and for those over the age of 65 years. Results: Although there were no significant univariate differences in breast cancer death rates by age group (P=0.94), more patients over the age of 65 years died from other causes (41/207 [20%] of those older than 65 years vs. 16/471 [3%] of those younger than 65 years;P<.001). In competing risks analyses, older age was associated with non-breast cancer death, whereas larger tumor size was associated with breast cancer death. PgR was positively, and nodal status negatively, associated with survival, regardless of type. In the older patient group, the competing risks analyses identified similar effects for age and tumor size; in addition, higher ER assay values were less likely to be associated with breast cancer death. Conclusions: With increased lifespan, there will be more breast cancer cases in women older than 65 years; we have shown that women in this group have more non-breast cancer deaths. It becomes important, then, to delineate differential effects of prognostic factors on competing causes of death.

Assessment of tumor size for multifocal primary breast cancer.

AbstractBackground: Tumor size affects the choice of surgical procedure and patient prognosis. It is standardly assessed as the largest unidimensional measurement and, for multifocal disease, as the largest size of the largest focus. We examine some different methods of assessing tumor size: the standard method; the sum of the largest sizes for all foci; surface area; and volume. Methods: Data for a cohort of 678 primary invasive breast cancer patients accrued from 1971 to 1990 were updated to 1996; there were 571 patients with unifocal disease and 107 patients with multifocal disease. We used step-wise Cox regression to investigate the effects on time to death of the prognostic factors tumor size (estimated in one of the four ways), age, nodal status, ER, PgR, adjuvant radiotherapy, adjuvant hormonal therapy, and adjuvant chemotherapy. We also examined the association between tumor focality and nodal status. Results: For all patients, tumor size was included in the multivariate model, regardless of estimation method. For patients with multifocal disease, tumor size was included in the final model only when it was estimated as the total surface area (P=.03) or volume (P=.01) of the foci. More multifocal patients were N+ (P=.056). Conclusions: For patients with multifocal disease, the significance association with mortality for total surface area or volume may imply a biologic relevance or mode of tumor activity for the foci.

In Situ Duct Carcinoma of the Breast: Clinical and Histopathologic Factors and Association with Recurrent Carcinoma

There has been a recent increase in the diagnosis of in situ duct carcinoma of the breast (DCIS) as a result of mammographic screening. DCIS is heterogeneous in appearance and likely in prognosis. There is no generally accepted model to predict progression to invasive carcinoma. We investigated the prognostic effect of clinical presentation and pathologic factors for women diagnosed with primary DCIS. A cohort of 124 patients was accrued between 1979 and 1994 and was followed to 1997; 78 had DCIS detected mammographically, and 88 underwent lumpectomy alone. In this article, we provide details about characteristics affecting the choice of primary therapeutic modality, and we examine the effects of factors on progression for the two patient subgroups. Presentation with bloody nipple discharge was associated with a significant increase in DCIS recurrence (p = 0.07). The pattern of duct distribution was important: DCIS in which the involved ducts were more widely separated had a significantly greater recurrence of DCIS than when the involved ducts were more concentrated (p = 0.08 for mammographically detected DCIS, p = 0.07 for patients who underwent lumpectomy alone). For mammographically detected DCIS, younger patients had more DCIS recurrence (p = 0.07). We found considerable heterogeneity in nuclear grade; 50% of patients exhibited more than one grade. Nuclear grade, necrosis, and architecture were not significantly associated with either recurrence of DCIS or development of invasive carcinoma. Longer follow‐up will allow further evaluation of the prognostic relevance of the factors assessed.

Factors associated with local breast cancer recurrence after lumpectomy alone

AbstractBackground: The purpose was to determine the rate of local breast relapse in patients with breast cancer uniformly treated with partial mastectomy but without postoperative radiotherapy and without systemic adjuvant therapy. We also systematically examined the factors associated with local recurrence to determine whether a low-risk subgroup existed. Methods: A retrospective review of a prospectively followed (median, 8 years) cohort of 293 patients was performed. The end-point was ipsilateral local breast cancer recurrence. The patients age, tumor size, nodal status, estrogen and progesterone receptor status, histology, and tumor and nuclear grade were studied, as were the presence and amount of carcinoma in situ and the presence of tumor emboli using univariate Kaplan-Meier and Cox step-wise multivariate analyses. Results: The overall local relapse rate was 26% (77 recurrences). Univariate factors significantly associated with decreased local relapse included older age, negative nodes, small tumor size, positive estrogen receptor status, and absence of tumor emboli. Significant multivariate variables were age, nodal status, estrogen receptor status, absence of comedo carcinoma in situ, and tumor emboli. A low-risk subgroup of 66 patients was defined with a 6% 10-year local recurrence rate. Conclusion: Important patient and tumor variables associated with local breast cancer relapse after breast-conserving surgery can define a low-risk subgroup.

A comparison of all-subset Cox and accelerated failure time models with Cox step-wise regression for node-positive breast cancer

SummaryClinical studies usually employ Cox step-wise regression for multivariate investigations of prognostic factors. However, commercial packages now allow the consideration of accelerated failure time models (exponential, Weibull, log logistic, and log normal), if the underlying Cox assumption of proportional hazards is inappropriate. All-subset regressions are feasible for all these models.We studied a group of 378 node positive primary breast cancer patients accrued at the Henrietta Banting Breast Centre of Womens College Hospital, University of Toronto, between January 1, 1977, and December 31, 1986. 85% of these patients had complete prognostic factor data for multivariate analysis, and 96% of the patients were followed to 1990. There was evidence of marked departures from the proportional hazards assumption with two prognostic factors, number of positive nodes and adjuvant systemic therapy. The data strongly supported the log normal model. The all-subset regressions indicated that three models were similarly good. The variables 1) number of positive nodes, 2) tumour size, and 3) adjuvant systemic therapy were included in all three models along with one of three biochemical receptor variables 1) ER, 2) combined receptor (ER- PgR-; ER+ PgR-; ER- PgR+; ER+ PgR+; or 3) PgR.Better multivariate modeling was achieved by using quantitative prognostic factors, a check for appropriate underlying model-type, and all-subset variable selection. All-subset regressions should be considered for routine use with the many new prognostic factors currently under evaluation; it is very possible that there may not be a single model that is substantially better than others with the same number of variables.

Survival from primary breast cancer after routine clinical use of mammography.

Clinical trials indicate that mammography provides a substantial breast cancer survival benefit; however, there is a need to demonstrate that this benefit extends to clinical practice and to determine the extent that current reductions in mortality are attributable to regular screening or adjuvant systemic therapy. Mammography was used routinely at our institution across a broad age range, in an era when most patients received no adjuvant systemic therapy. We examined breast cancer survival for a cohort of 678 stage I–III primary invasive breast cancer patients accrued from 1971 to 1990, and followed to 1996; 18% received adjuvant hormonal therapy and 15% received adjuvant chemotherapy. There were 61 women less than 40 years old; 136, 40–49 years; 341, 50–69 years; 140, ≥70 years. Factors available for multivariate investigations were age (years), tumor size (cm), nodal status (N−, N×, N+), ER (fmol/mg protein), PgR (fmol/mg protein), adjuvant radiotherapy (no, yes), adjuvant hormonal therapy (no, yes), and adjuvant chemotherapy (no, yes). Forward stepwise multivariate regression with log‐normal survival analysis was used to examine the effects of these factors on disease‐specific survival. Ten‐year survival by tumor size was adjusted for the effects of other significant factors. For women less than 40 years of age, 10‐year survival at the T1a, T1b, T1c, and T2 cut‐points for tumor size is, respectively, 0.77, 0.74, 0.67, 0.44; for 40–49 years it is 0.92, 0.90, 0.85, 0.62; for 50–69 years it is 0.81, 0.79, 0.75, 0.62; for ≥70 years it is 0.84, 0.81, 0.73, 0.44. With routine use of clinical mammography and up to 26 years of follow‐up, we found breast cancer survival to be significantly better (p≤ 0.05) for all women with smaller tumors and that survival indicated a change in natural disease history with early detection. The Canadian National Breast Screening Study (NBSS) controls had significantly smaller tumors (p < 0.001) than our patients, which may indicate access to mammography outside of the NBSS that reduced the apparent survival benefit for clinical trial mammography.

Pathologic Characteristics of Breast Cancer that Predict for Local Recurrence After Lumpectomy Alone

▪Abstract: Breast conservation surgery (BCS) plus irradiation has been shown to be equivalent to mastectomy in controlling ipsilateral breast cancer recurrence. The purpose of this study is to evaluate the factors that determine the rate of local recurrence in a group of patients treated with partial mastectomy without postoperative radiation, adjuvant hormonal therapy, or chemotherapy. We also assess the role of standard pathologic features, specifically lymphovascular invasion (LVI) in identifying high‐ and low‐risk subsets of patients. We have a cohort of 293 patients treated with partial mastectomy followed prospectively for a median of 8 years. Data collected included patient’s age, tumor size, tumor morphology, tumor grade, the extent of ductal carcinoma in situ (DCIS), the presence of LVI, lymph node status, and hormone receptors. Statistical analyses carried out were Kaplan–Meier plots with Wilcoxon (Peto–Prentice) test statistics for univariate analysis and Cox stepwise regression for multivariate analysis; the end point was local recurrence. The relapse rate in this cohort was 26%. In univariate analysis the significant factors associated with prolonged disease‐free survival included older age, negative nodes, positive estrogen receptor (ER) status, and absence of LVI. Small tumor size was significant only in the univariate analysis. In the multivariate analysis, absence of comedocarcinoma entered the model in addition to the other variables. If the variables are stratified, a group of 66 patients with 6% local recurrence rate was identified. These were node‐negative women 50 years of age with no LVI, no comedo DCIS, and ER‐positive tumors. This study clearly indicates the important role of pathologic parameters in assessing the risk of recurrence. ▪

Assessment of treatment for patients with primary ductal carcinoma in situ in the breast

AbstractBackground: Current mammographic technology has resulted in increased detection of ductal carcinoma in situ (DCIS). It is necessary to assess which patients presenting with DCIS are good candidates for breast conservation and which of these patients should receive adjuvant radiation. Methods: We accrued clinical data for 124 patients with a primary diagnosis of DCIS from 1979 through 1994. Primary therapy was a mastectomy for 18 patients, and a lumpectomy for 106 patients. Only 18 of the latter group of patients received adjuvant radiotherapy. For the 88 lumpectomy-alone patients (median follow-up, 5.2 years), we evaluated the effects of clinical (age and initial presentation) and pathologic (nuclear grade, architecture, parenchymal involvement, calcifications, and measured margins) factors on recurrence of DCIS or the development of invasive breast cancer. Results: Patients who underwent lumpectomy with or without adjuvant radiotherapy (median follow-up, 5.0 years) were significantly more likely to have recurrence of DCIS (P=.05) than those who underwent mastectomy (median follow-up, 6.7 years): 18% (19/106) versus 0% (0/18), respectively; lumpectomy-alone patients experienced a 19% (17/88) rate of DCIS recurrence. All recurrent DCIS was ipsilateral. For lumpectomy-alone patients, the factors associated with ipsilateral recurrence of DCIS were extent of involvement of the parenchyma (P=.01, for univariate;P=.07, for multivariate) and initial presentation (P=.05, for univariate;P=.07, for multivariate). Eleven lumpectomy-alone patients developed invasive breast cancer (6 ipsilateral, 5 contralateral); none of the 18 lumpectomy patients who received adjuvant radiation developed invasive disease. None of the factors investigated, including primary surgery and adjuvant radiotherapy, were associated with a significant effect on the development of invasive disease. Conclusions: Longer follow-up is required to determine if the benefits of either mastectomy or radiotherapy following lumpectomy persist. There is a suggestion that patients under 40 years of age or women who present with nipple discharge might be considered for either adjuvant radiotherapy following lumpectomy or a simple mastectomy.