5-year Breast Cancer-specific Survival Research Articles

Abstract P4-09-17: Case-Matching Study Comparing Outcome of Unilateral and Synchronous Bilateral Breast Cancer

Abstract Background: Several retrospective studies have demonstrated worse outcomes for patients with synchronous bilateral breast cancer (SBBC) compared to unilateral breast cancer. This study aimed to determine whether SBBC outcomes can be estimated accurately from the characteristics of the higher-risk cancer. Material and Methods: In the province of British Columbia, Canada, women newly diagnosed with invasive breast cancer between 1989 and 2000, without metastatic or inflammatory presentation, were identified: 207 with SBBC (< 2 months apart) and 15,497 with unilateral breast cancer. Their breast cancer-specific survival (BCSS) outcomes were compared. Using 10-year BCSS estimates, the higher-risk cancer of each SBBC was determined. The priority sequence of matching of the prognostic and predictive variables was: positive lymph node number, primary tumor size, age, grade, lymphovascular invasion status, estrogen receptor status, type of local therapy, margin status, treating clinic, diagnosis year and systemic therapy use. A software program was employed on the 15,497-case cohort to select three unilateral cases that matched the maximum number of variables for the higher-risk cancer of each SBBC case, thereby generating a matched 621-case unilateral cohort. Results: At a median follow-up of 10.2 years, the 10-year BCSS was significantly lower for the SBBC cohort, 71% (95%CI 63 — 77) than for the 15,497-case unilateral cohort, 81.1% (95%CI 80.5 — 81.8) (p < 0.001). However, the SBBC cohort had significantly higher median age and stage at presentation. After the matching, there was no significant difference for the eleven variables between the SBBC cohort and the 621-case unilateral cohort. The 10-year BCSS was 71% (95%CI 63-77) for the SBBC cohort and 74% (95%CI 69-77) for the matched 621-case unilateral cohort. Discussion: BCSS was similar between the SBBC cohort and the unilateral cohort matched to the higher-risk SBBC. Therefore, the outcome of women with SBBC is best estimated from their higher-risk cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-17.

Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study

The objective of this study is to define the survival outcomes associated with distinct molecular phenotypes defined by immunohistochemical staining of paraffin-embedded tissues among invasive breast cancer cases identified from the Nurses' Health Study (NHS). Tissue microarrays were constructed from archived tissue blocks of women diagnosed with breast cancer in the NHS (1976-1997). Invasive non-metastatic breast cancer tumors (n = 1,945) were classified into 1 of 5 molecular phenotypes based on immunohistochemistry assays for estrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and grade. Survival outcomes were estimated using the Kaplan-Meier product limit method. Cox-proportional hazards models were fitted to determine the association of molecular phenotype with survival outcomes after adjusting for covariates. 1,279 (65.8%) tumors were classified as luminal A, 279 (14.3%) as luminal B, 95 (4.9%) as HER2 type, 203 (10.4%) as basal-like and 89 (4.6%) tumors were unclassified. The 5-year breast cancer-specific survival estimates for women with luminal A, luminal B, HER2-type, basal-like and unclassified tumors were 96, 88, 81, 89 and 85%, respectively. In the multivariable model, compared to cases with luminal A tumors, cases with luminal B (HR 1.90, 95% CI 1.33-2.71), HER2-type (HR 1.36, 95% CI 0.87-2.12), basal-like (HR 1.58, 95% CI 1.05-2.39) and unclassified (HR 1.38, 95% CI 0.87-2.20) tumors had higher hazard of breast cancer death. Similar trends were observed for both overall and recurrence-free survival. In conclusion, compared to women who have luminal A tumors those with luminal B, HER2-type, basal-like and unclassified tumors had a worse prognosis, when tumor subtype was defined by immunohistochemistry. This method may provide a cost-effective means of determining prognosis in the clinical setting.

Predictors of Local Recurrence in a Population-Based Cohort of Women with Ductal Carcinoma In Situ Treated with Breast Conserving Surgery Alone

To identify prognostic indicators of local recurrence (LR) in patients with ductal carcinoma in situ (DCIS) of the breast treated with breast conserving surgery (BCS) alone. A retrospective study was conducted of all women with pure DCIS, diagnosed 1985-1999, referred for tertiary oncologic opinion in British Columbia, treated with BCS without adjuvant radiotherapy. Kaplan-Meier local control (LC) and breast cancer specific survival (BCSS) estimates for the entire group were plotted. Stratified analyses identified subgroups with high Kaplan-Meier 10-year LR. Cox multivariate modeling was used to assess predictors of LR. Kaplan-Meier BCSS rates were compared between two cohorts: those who experienced LR and those who did not have LR. A total of 460 women comprised the study cohort. Median follow-up was 9.4 years. The 15-year LC and BCSS rates were 82% and 97%, respectively. Stratified analyses of LR identified comedo histology, high nuclear grade, tumor size >4 cm or indeterminate size, and positive margins to be associated with significantly higher LR risk, with 10-year LR risks approximating 15-30%. The 10-year BCSS rates for the LR group were 94% compared with 99% for the NoLR group. On Cox regression modeling, high nuclear grade, the presence of comedocarcinoma, and positive margins were significant factors for higher risk of LR. Women with DCIS treated with BCS alone had higher LR risk, and those with a LR were more likely to die of breast cancer. Optimal local treatment is mandatory to minimize the risk of breast cancer death for women with this curable disease.

Diverse Associations between ESR1 Polymorphism and Breast Cancer Development and Progression

To test the hypothesis that polymorphisms of ESR1, the gene encoding estrogen receptor alpha (ERalpha), are associated with susceptibility, clinical phenotype, and progression of breast cancer. A case-control study was done on 940 patients with incident breast cancer and 1,547 healthy female controls. Fifteen single-nucleotide polymorphisms (SNP) selected from chr6:152,170,379-152,466,100 (exons 1-8 of the ESR1 gene, excluding flanking sequences), reflecting major polymorphisms of this gene, were genotyped. Frequencies of SNPs were compared between cases and controls to identify SNPs associated with cancer susceptibility and between cases with different clinical phenotypes to determine the role of ESR1 polymorphism in cancer progression. SNPs located in one cluster in intron 1 and one haplotype, based on these SNPs, showed a significant association with breast cancer susceptibility. The tumorigenic contribution of these intron 1 SNPs was more obvious in combination with reproductive risk factors (P for interaction <0.05). One of these intron 1 SNPs was also significantly associated with low ERalpha expression in tumors. Interestingly, the same intron 1 SNPs showed a correlation with worse clinical phenotypes, including poor differentiation of tumor cells and a late stage. These intron 1 SNPs also showed a significant association with the 5-year breast cancer-specific survival rate of patients, but had opposite effects in ERalpha-negative and ERalpha-positive early-stage patients. Our findings provide support for diverse roles of ESR1 polymorphism in determining susceptibility in different stages of breast cancer. The differences between the important ESR1 SNPs identified in Chinese women in this study and those identified in studies on Western women with breast cancer suggest different roles of ERalpha in these two populations.

Corrections: 2009 San Antonio Breast Cancer Symposium Abstracts

Corrections: 2009 San Antonio Breast Cancer Symposium Abstracts

Outcomes of Node-Negative Breast Cancer 5 Centimeters and Larger Treated With and Without Postmastectomy Radiotherapy

The role of adjuvant postmastectomy radiotherapy (PMRT) remains controversial for the rare presentation of pT3pN0cM0 breast cancer. The present analysis examined locoregional recurrence (LRR) and breast cancer-specific survival (BCSS) in pT2 = 5.0-cm and pT3 >5.0-cm tumors treated with mastectomy, stratified by PMRT use. Between January 1, 1989 and December 31, 2000, the British Columbia provincial database yielded 100 node-negative patients with tumors ≥ 5 cm of 19,846 nonmetastatic breast cancer patients (0.5%). Of these 100 patients, 44 (44%) had received adjuvant PMRT. The PMRT group contained significantly more pT3 >5-cm cases (p = 0.001) and margin-positive cases (p = .03). With a median follow-up of 10 years, the cumulative 10-year LRR rate was 2.3% (95% confidence interval, 0.2-10.5) in the PMRT group vs. 8.9% (95% confidence interval, 3.2-18.2) in the no-PMRT group (p = .2). Regarding LRR in the no-PMRT group, all patients had Grade 3 histologic features (LRR 17%, 5 of 29) and had not received hormonal therapy (LRR 15%, 5 of 34). The 10-year breast cancer-specific survival rate was 85.8% (95% confidence interval 71.0-93.4) in the PMRT group vs. 74.6% (95% confidence interval 59.9-84.5) in the no-PMRT group (p = .2). On multivariate analysis, adjusted for the prognostic and predictive variables, PMRT did not significantly improve the LRR or breast cancer-specific survival rates. The present study demonstrated a low LRR rate for node-negative breast cancer ≥ 5 cm. Our results indicate that PMRT should be considered for Grade 3 histologic features and patients not undergoing hormonal therapy.

Audit of local recurrence following breast conservation surgery with 5-mm target margin and hypofractionated 40-Gray breast radiotherapy for invasive breast cancer

The risk of ipsilateral breast tumour recurrence (IBTR) following breast conservation surgery (BCS) for invasive breast cancer (IBC) and radiotherapy is dependent on patient-, tumour- and treatment-related variables. In the Cambridge Breast Unit, breast conserving surgery has been performed with a target radial margin of 5 mm for IBC, in combination with 40-Gy hypofractionated (15 fractions) breast radiotherapy, since 1999. An audit was performed of cases treated between 1999 and 2004. A total of 563 patients underwent BCS for invasive breast cancer with 90.4% receiving radiotherapy (RT) and 60.4% of patients receiving boost RT (3 fractions of 3-Gy). After a median follow-up of 58 months, five of the 563 (0.9%) patients developed IBTR. The 5-year actuarial IBTR rate was 1.1%. In terms of distant disease recurrence (DDR), 29 of the 563 (5.2%) had DDR during follow-up, giving a 5-year actuarial DDR rate of 5.4%. The 5-year breast cancer specific survival was 95%, with the poorer NPI groups having worse breast cancer specific survival (Log-rank, P<0.0001). More importantly, patients with IBTR had a shorter breast cancer-specific survival than those who were IBTR-free (Log-rank, P<0.0001). Our treatment regimen, combining BCS with a 5-mm target margin and hypofractionated 40-Gy RT, results in an extremely low rate of IBTR, and compares favourably with the target IBTR rate of <5% defined by the Association of Breast Surgeons (ABS) at BASO guidelines.

Evaluation of the 70-gene prognosis MammaPrint signature for the prediction of prognosis of breast cancer independently from histologic grade.

561 Background: Histologic grade is one of the strongest prognostic factors for breast cancer patients. In this study we assessed the prognostic value of the 70-gene prognosis signature (MammaPrint), validated for node-negative and -positive patients, for grade (G) 1-3 breast cancer. Methods: 1630 tumor samples of pT1-3 N0-1 breast cancer patients from 7 previously reported studies were analyzed and classified by MammaPrint as low or high risk. 10-year breast cancer-specific survival (BCSS) and distant disease-free survival (DDFS) was analyzed using Kaplan-Meier survival curves and multivariate Cox regression analyses. Results: Of 1,630 patients 392 (24%) were classified as G1 (21% 70-gene high risk), 646 (40%) as G2 (42% high risk) and 592 (36%) as G3 (86% high risk), respectively. At 10 years of follow-up, the 70-gene signature accurately distinguished low-risk from high-risk tumors for all histologic grades: within G1 tumors, absolute BCSS was 91% for 70-gene low risk and 82% for 70-gene high risk patients, HR 2.6 (95%CI 1.1-5.7), p = 0.02. Within G2 survival was 88% (low risk) and 68% (high risk), HR 3.3 (2.1-5.3), p < 0.01 and within G3 survival was 86% (low risk) and 64% (high risk), HR 3.4 (1.6- 7.2), p < 0.01. For DDFS: G1 HR 2.8 (1.5-5.4), p < 0.01), G2 HR 2.2 (1.5-3.2), p < 0.01 and G3 HR 2.4 (1.3-4.5), p < 0.01. Multivariate analysis with known prognostic factors and adjuvant therapy including histologic grade and the signature confirmed MammaPrint as strongest independent prognostic factor for 10-year survival (HR BCSS 2.8 [1.8-4.3], p < 0.01) and DDFS HR 2.2 [1.5-3.2], p < 0.01). Limited to chemotherapy-untreated patients only, results were similar (multivariate HR BCSS 2.3 [1.5-3.8], p < 0.01 and DDFS HR 1.9 [1.3-2.8], p < 0.01). Conclusions: The 70-gene MammaPrint signature provides independent prognostic information for all histological grades. Of note, “G1/70-gene high-risk” patients had a relatively poor 10-year BCSS of 82%, and therefore may be treated aggressively. In contrast, “G3/70-gene low-risk” patients achieved a 10-year BCSS of 86%, where adjuvant chemotherapy might be of limited benefit. This study confirms the clinical value of the 70-gene signature for all histological grades. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Agendia Agendia

Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients.

Despite increased demand for contralateral prophylactic mastectomy (CPM), the survival benefit of this procedure remains uncertain. We used the Surveillance, Epidemiology, and End Results database to identify 107 106 women with breast cancer who had undergone mastectomy for treatment between 1998 and 2003 and a subset of 8902 women who also underwent CPM during the same period. Associations between predictor variables and the likelihood of undergoing CPM were evaluated by use of chi(2) analyses. Risk-stratified (estrogen receptor [ER] status, stage, and age) adjusted survival analyses were performed by using Cox regression. Statistical tests were two-sided. In a univariate analysis, CPM was associated with improved disease-specific survival (hazard ratio [HR] of death = 0.63, 95% confidence interval [CI] = 0.57 to 0.69; P < .001). Risk-stratified analysis showed that this association was because of a reduction in breast cancer-specific mortality in women aged 18-49 years with stages I-II ER-negative cancer (HR of death = 0.68, 95% CI = 0.53 to 0.88; P = .004). Five year-adjusted breast cancer survival for this group was improved with CPM vs without (88.5% vs 83.7%, difference = 4.8%). Although rates of contralateral breast cancer among young women with stages I-II disease undergoing CPM were independent of ER status, women with ER-positive tumors in the absence of prophylactic mastectomy also had a lower overall risk for contralateral breast cancer than women with ER-negative tumors (0.46% vs 0.90%, difference = 0.44%; P < .001). CPM is associated with a small improvement in 5-year breast cancer-specific survival mainly in young women with early-stage ER-negative breast cancer. This effect is related to a higher baseline risk of contralateral breast cancer.

Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up

Triple-negative breast cancer (TNB) has poor prognosis and moreover patients with TNB do not benefit from established targeted drugs with endocrine therapy or trastuzumab. The aim of the study was to analyze the prevalence of candidate biomarkers in tumors from patients with TNB. Tissue microarrays were prepared from primary tumors from premenopausal breast cancer patients (500/564) randomized to adjuvant tamoxifen or no adjuvant treatment. Immunohistochemical (IHC) staining included ER, PR, HER2, epidermal receptor growth factor (EGFR), vascular endothelial growth factor A (VEGF-A), and vascular endothelial growth factor receptor 2 (VEGFR2). EGFR and HER2 gene copy number was defined by fluorescence in situ hybridization (FISH). All patients were included in the descriptive analysis, but only untreated patients in the survival analysis. TNB was diagnosed in 96 patients and correlated significantly to low age, Nottingham histological grade (NHG) III, high Ki67-index, T2 tumors, node negativity, EGFR positivity, increased EGFR gene copy number and high VEGFR2 expression. TNB was an independent prognostic factor for decreased 5-year breast cancer specific survival (BCSS) (HR 2.0 (95% CI 1.1-3.6), P = 0.01), but not for 10-year BCSS. High VEGFR2 expression was significantly correlated to decreased BCSS in TNB patients. TNB was associated with decreased BCSS and clinicopathological characteristics of an aggressive tumor type. High VEGFR2 expression, EGFR expression, and EGFR gene copy number were significantly correlated to TNB, supporting their role as putative candidate biomarkers for selection of targeted therapy in TNB.

Metastatic Potential of T1 Breast Cancer can be Predicted by the 70-gene MammaPrint Signature

Mammographic screening and increased awareness has led to an increase in the detection of T1 breast tumors that are generally estimated as having low risk of recurrence after locoregional treatment. However, even small tumors can metastasize, which leaves us with the question for the necessity of adjuvant treatment. Therefore, additional prognostic markers are needed to tailor adjuvant systemic treatment for these relatively low-risk patients. The aim of our study was to evaluate the accuracy of the 70-gene MammaPrint signature in T1 breast cancer. We selected 964 patients from previously reported studies with pT1 tumors (<or=2 cm). Frozen tumor samples were hybridized on the 70-gene signature array at the time of the initial study and classified as having good prognosis or poor prognosis. The median follow-up was 7.1 years (range 0.2-25.2). The 10-year distant metastasis-free (DMFS) and breast cancer specific survival (BCSS) probabilities were 87% (SE 2%) and 91% (SE 2%), respectively, for the good prognosis-signature group (n = 525), and 72% (SE 3%) and 72% (SE 3%), respectively, for the poor prognosis-signature group (n = 439). The signature was an independent prognostic factor for BCSS at 10 years (multivariate hazard ratio [HR] 3.25 [95% confidence interval, CI, 1.92-5.51; P < .001]). Moreover, the 70-gene MammaPrint signature predicted DMFS at 10 years for 139 patients with pT1ab cancers (HR 3.45 [95% CI 1.04-11.50, P = .04]). The 70-gene MammaPrint signature is an independent prognostic factor in patients with pT1 tumors and can help to individualize adjuvant treatment recommendation in this increasing breast cancer population.

The 70-Gene Profile (MammaPrintTM) Is an Independent Predictor of Breast Cancer Specific Survival for Women 65 Years of Age or Older.

Abstract Background: One-half of all new breast cancer diagnoses occur in women age 65 years or older. In this age group, the use of adjuvant chemotherapy is largely influenced by co-morbidity and little is known about the applicability of prognostic multi-gene assays. The 70-gene profile (MammaPrint) is an independent prognostic indicator in early breast cancer, however, its performance in women with breast cancer 65 years or older has not been systematically studied.Methods: Women 65 years or older who were diagnosed at the Jules Bordet Institute and the Netherlands Cancer Institute between 1987 and 2003 with primary breast cancer with 0-3 involved lymph nodes who received either no adjuvant systemic therapy or adjuvant hormonal therapy alone were selected. MammaPrint test results were compared with clinical-pathological risk assessment using Adjuvant!Online.Results: Of 204 women aged 65 years or older (median age 70 years), 129 (63.2%) were classified as genomic low risk and 75 (36.8%) as genomic high risk. After a median follow-up of 8.6 years (range 0.3-17.9), the 5- and 10-year breast cancer specific survival (BCSS) for the genomic low risk group was 96% (SE 2%) and 86% (SE 4%) versus 82% (SE 4%) and 66% (SE 6%) for the genomic high risk group (log-rank p=0.001). In univariate analysis, MammaPrint was prognostic for 5-year BCSS (HR=5.0, 95%CI 1.8-14.1, p=0.002) and 10-year BCSS (HR=3.1, 95%CI 1.6-6.0, p=0.001). In a multivariate model adjusted for 10-year risk predicted by Adjuvant!Online, MammaPrint was independently prognostic for 5-year BCSS (HR=4.4, 95%CI 1.6-12.7, p=0.005) and 10-year BCSS (HR=2.5, 95%CI 1.3-5.0, p=0.009). As in prior validation series, the performance of MammaPrint was time dependent, with improved prognostication for early BCSS (≤5 years).Conclusion: Although a smaller proportion of breast cancers diagnosed in women 65 years or older are classified as high-risk by MammaPrint, it is an independent prognostic indicator that may be useful to select patients that can safely forego adjuvant chemotherapy. Additional data from patients over 70 years of age will be available at the time of the meeting. If these data are confirmatory, the ongoing prospective MINDACT trial will be amended to include older women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4049.

Prediction of 10-Year Chemotherapy Benefit and Breast Cancer-Specific Survival by the 21-Gene Recurrence Score (RS) Assay in Node-Positive, ER-Positive Breast Cancer – An Update of SWOG-8814 (INT0100).

Abstract Background: A low 21-gene RS identifies patients with ER-positive breast cancer who do not appear to benefit from anthracycline-based chemotherapy (CAF) added to tamoxifen (T) despite positive axillary lymph nodes (Albain KS, et al. Lancet Oncology, In Press). However, in the low RS group, the lack of improvement by CAF in the 64% disease-free survival (DFS) at 10 years is not considered definitive evidence against the use of chemotherapy for conventionally-identified high risk patients. We conducted new DFS prediction analyses within nodal categories by RS over 10 years and assessed whether the assay has predictive utility for breast cancer specific survival (BCSS).Methods: RT-PCR analyses for the 21 gene RS assay were feasible in 148 patients on T from the parent trial treated and 219 on CAF followed by T, as previously described. In this update, we conducted 10-year DFS analyses within nodal categories 1-3+ and 4+ by the linear RS. For the exploratory analysis of BCSS, only deaths due to breast cancer were counted as events, censoring deaths due to other causes (such as late cardiovascular events) as well as patients alive at the last follow-up visit. The clinically-utilized (trichotomized) RS categories of low (&amp;lt;18), intermediate (18-30) and high (≥31) were used for the BCSS analysis, and log-rank p-values were stratified by nodes.Results: As with the previously reported 5-year DFS analysis by nodal status and linear RS, there was no apparent DFS benefit to CAF in the lower Recurrence Scores over 10 years for either the 1-3+ or 4+ nodal groups. Specifically (for both nodal groups), the 10-year DFS treatment curves overlapped for scores 0-10 and then started diverging at about RS=11, though any clinically meaningful CAF benefit for DFS was not evident until much higher Recurrence Scores. There was no BCSS benefit from CAF in either the low RS (log-rank p=0.56) or intermediate RS (log-rank p=0.89) categories, but CAF resulted in superior BCSS in the high RS category (log-rank p=0.033). The 10-year estimates for BCSS for low RS were 92% (95% CI 79%-97%) for T and 87% (95% CI 76%-93%) for CAF-T. In the intermediate RS, 10-year BCSS estimates were 70% (50%-83%) for T and 81% (67%-89%) for CAF-T; and in the high RS, 10-year BCSS estimates were 54% (38%-68%) for T and 73% (60%-82%) for CAF-T.Conclusions: These additional exploratory analyses reinforce our initial interpretation that anthracycline-based chemotherapy does not appear to benefit patients with either 1-3 or 4 or more positive nodes over 10 years, if their tumors have a low RS. A prospective study to confirm and extend these results has been proposed. New adjuvant treatment strategies for tumors with this distinct biology should be a high research priority.Funding: This study was supported by the National Cancer Institute (NCI #8814A-ICSC) and Genomic Health, Inc. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 112. NOTE: This abstract was accepted for presentation at the Symposium after the Abstract Book went to press.

Biological Subtypes and Risk of Second Primary Breast Cancer in Inflammatory Breast Cancer – Population Based Analysis from the California Cancer Registry.

Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Our group's recent study revealed that the 5-year breast cancer specific survival for IBC is 49%, an improved rate compared to historical studies (∼ 30%). This could be attributed to evolution in modern modalities of treatment including utility of transtuzumab. Given marginally improved survival, these women are also at risk for second breast cancers. Here we investigate the risk of second breast cancer in IBC compared to the general population.Methods: We identified 75,039 IBC, LABC and non-T4 female breast cancer cases in the California Cancer Registry during the period of 1999-2005. We excluded synchronous tumors (cancer diagnosed &amp;lt;6 months from first breast cancer diagnosis). Standardized incidence ratio (SIR) with 95% CI is used to calculate the risk of second breast cancer by comparison to underlying general population.Results: A total of 1488 second breast cancer patients were identified, including 60 with a first diagnosis of IBC, 26 with a first diagnosis of LABC, and 1402 with a first diagnosis of non T-4 breast cancer. The risk of second breast cancer in IBC compared to the underlying population at risk was observed to be highest in IBC [SIR= 4.12 (3.14-5.30)] followed by LABC [SIR= 1.95 (1.28-2.86)], and non-T4 [SIR= 1.16 (1.10-1.23)] cases. Patients with IBC were more likely to be [HR-/HER2+] (43.8%) compared to LABC (33.3%) and non-T4 (8.7%) [p=&amp;lt;0.0001]. IBC and LABC were also increasingly associated with contralateral breast cancer (96%).Table-1: Risk of second breast cancer compared to general population by classification of first breast cancer Cohort sizeObserved 2nd breast cancerExpected 2nd breast cancerSIR (95%CI)IBC14746014.574.12 (3.14-5.30)LABC11032613.321.95 (1.28-2.86)Non-T472,46214021205.851.16 (1.10-1.23) Table-2: Hormone Receptor/Her2-neu status, subtype, laterality of second breast cancer by classification of first breast cancer £Receptor status of the first tumor*IBCLABCNon-T4TotalHR+/Her2+147(17%)123(20%)6405(15.5%)6675(15.7%)HR-/Her2+217(25%)98(16%)2713(6.6%)3028(7.1%)HR+/Her2-318(36.5%)268(43.8%)26,680(65%)27,266(64%)HR-/Her2-187(21.5%)124(20.2%)5303(12.9%)5614(13.2%)Receptor status of the second tumor** HR+/Her2+2 (6.2%)4 (26.7%)97 (12.6%)103 (12.6%)HR-/Her2+14 (43.8%)5 (33.3%)67 (8.7%)86 (10.5%)HR+/Her2-11 (34.4%)6 (40%)468 (60.6%)485 (59.2%)HR-/Her2-5 (15.6%)0 (0%)140 (18.1%)145 (17.7%)Subtypes of the 2nd primary breast tumor*** OtherIBC11(18.3%)2(5%)13(21.7%)33(55%)LABC5(19%)1(4%)11(42.4%)9(34.6%)Non-T425(1.8%)8(0.5%)482(34.4%)887(63.2%)Contralateral Breast cancer58(96.6%)25(96.1%)1165(83%)1484£ p value &amp;lt;0.0001 for all comparisons, *43% of data missing;** 49% of data missing;*** 8% of data missing.Conclusions: HR-/HER2+ biologic subtype of IBC was increasingly associated with development of second breast cancers and majority of them (96%) involved the contralateral breast with possible implications for IBC treatment. Among the investigated breast cancer subtypes IBC was associated with the highest risk of second breast cancers compared to the underlying population reinforcing IBC as an unique biologic entity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2056.

Use of Receiver Operating Characteristic (ROC) Analysis To Determine the Most Optimal Prognostic Threshold for Adjuvant! in Lymph Node Negative Breast Cancer Patients &amp;lt; 55 Years.

Abstract Background: Adjuvant!1 is a web based tool to predict the 10-year relapse free survival (RFS), breast cancer specific survival (BCSS) and overall survival (OS) probabilities using age, tumor size (pT), lymph node status (pN), histological grade (Grade 1-3), Estrogen receptor (ER) status in the estimation. A challenge is to find optimal cut-off values of the Adhuvant probabilities to compare the predictions with other prognostic factors.Patients and methods: In the Dutch nationwide Multicenter Morphometric Mamma Carcinoma Project 3472 patients have been enroled2, of which 516 &amp;lt;55 years with T1-3N0M0 underwent surgery and local radiation therapy when indicated. Adjuvant systemic treatment was not given according to the Dutch guidelines at that time. Median follow-up is 10 years. The 10-year RFS, BCSS and OS probabilities were evaluated with Adjuvant! Since these estimated predicted probabilities are continuous, optimal thresholds can be evaluated by the Receiver Operating Characteristic (ROC) analyses. Concordances between the Adjuvant predicted outcomes and, classical prognosticators were evaluated by the Spearman-correlation test.Results: The optimal cut-points for Adjuvant-RFS, Adjuvant-BCSS and Adjuvant-OS were 62% (Area Under the Curve=AUC==0.603, p=0.0004), 86% (AUC=0.635, p=0.0001) and 72% (AUC=0.598, p=0.0002) respectively. Using these thresholds, a moderate correlation was found between all the Adjuvant! endpoints and pT, Grade 1-3 and ER status (r=0.34 – 0.63). In the univariate survival analysis (Kaplan Meier) the above Adjuvant thresholds were highly prognostic. For Adjuvant-RFS &amp;gt;63/≤63 the 14-year survival was 77% and 64% respectively (p=0.001; log-rank). Moreover, for Adjuvant-BCSS (≥86/&amp;lt;86) the corresponding numbers were 82% and 67% ( P &amp;lt; 0.0001; log-rank). For Adjuvant-OS (≥72/&amp;lt;72) the survivals were 77% and 64% respectively (p&amp;lt;0.0001; log-rank). With multivariate analyses, Adjuvant! variables were part of the model only for BCSS and OS. However, Grade1-3 was prognostically stronger than Adjuvant! regarding both BCSS and OS. Furthermore, when the three features that constitute grade (tubular formation, nuclear atypia and mitosis count), only the latter was included in the final model.Discussion: ROC analysis can obtain optimal prognostic threshold values from web-based prognostic tools using time dependent endpoints3. A high grade of dependency between Adjuvant! and its’ underlying variables must be taken into account when the multivariate model is put up. Mitotic activity in the tumor seems to overrule Adjuvant!. This should be further explored.1 www.adjuvantonline.com2 Baak JPA, et al.: Pathol Res Pract 185:664-70, 19893 Zlobec I, et al.:J Clin Pathol 60:1112-1116, 2007. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3178.

Evidence-Based Breast Cancer Prevention: The Importance of Individual Risk

Widespread use of screening mammography has been the mainstay of breast cancer prevention in the United States for the past 25 years. In this issue, the USPSTF has made major changes to its recomme...

Loco-regional treatment in metastatic breast cancer patients: Is there a survival benefit?

A number of studies have recently demonstrated a survival benefit in stage IV breast cancer patients following surgical resection of the primary tumor. Here, we investigate the relationship between loco-regional treatment and survival in patients with metastatic breast cancer and evaluate the impact of different loco-regional treatments. We conducted a systematic review of the literature using PubMed to analyze studies with the following criteria: Type of loco-regional treatment (surgery alone or combined with radiation, radiotherapy), overall survival, progression-free survival, selection factors for local treatment, and complication rates. Thirteen studies evaluated the effect of loco-regional treatment on overall survival with overall median survival increasing from a range of 12.6-28.3 months among patients without surgery to a range of 25-42 months among patients with surgery. In addition, six studies reported a 3-year survival benefit of 28-95% and 17-79% in women with and without locoregional therapy respectively. Two studies did not find any improvement in overall survival. One study found an improvement in 5-year breast cancer-specific survival of 27% with negative surgical margins versus 12% with no surgery. Three studies reported an advantage in progression-free survival in the treatment group compared with the non-treatment group. Loco-regional treatment for breast cancer patients with distant metastases at diagnosis is an important issue because of possible improvement of survival or disease-free survival. The possibility of surgery and/or radiotherapy following induction chemotherapy should be weighed and left to individual practice. Participation in randomized controlled trials should be encouraged.

Surgery versus primary endocrine therapy for elderly women with estrogen receptor-positive early operable primary breast cancer: Survival analysis and correlation with oestrogen receptor positivity

612 Background: A recent Cochrane review of seven randomised trials involving 1,446 elderly women (unselected for oestrogen receptor (ER) status) has shown no significant difference in overall survival between surgery (with or without adjuvant tamoxifen) and primary endocrine therapy using tamoxifen. We now report results of a large series from a single centre with a dedicated elderly breast cancer service, with long term follow-up. Methods: During a period of &gt; 20 years, 1,031 elderly (&gt; 70 years) women with ER positive (H-score &gt;50) early operable primary breast cancer received either surgery (with or without adjuvant endocrine therapy) (N = 436) or primary endocrine therapy (N = 595) (&gt;80% using tamoxifen) as initial treatment, with complete follow-up information till deaths. The initial treatment was decided based on fitness for surgery and patient choice. Analysis was carried out on breast cancer specific survival and degree of ER positivity. Results: After a median follow up of 49 months (range 0 - 261 months), patients between 70 - 80 years, treated by surgery, had better 5-year breast cancer specific survival compared to their counterparts treated by primary endocrine therapy (95% versus 85%; p &lt; 0.001). For patients &gt; 80 years, there was however no statistical difference between the two groups (90% versus 90%; p = 0.813). The median survival has not reached yet in all groups. Patients in the latter group (&gt; 80 years) were found to have a higher chance of having strongly ER positive tumours (57% versus 50% in patients between 70 - 80 years with H-score &gt;200; p- &lt; 0.02). Conclusions: In a selected group of elderly women (&gt; 80 years) who tend to have strongly ER positive tumours, surgery and primary endocrine therapy did not appear to produce any difference in breast cancer specific survival. This subject is currently being investigated in a national randomised trial in the UK. No significant financial relationships to disclose.

Early determination of metastatic potential in breast cancer: The 70-gene signature in small tumors

518 Background: Small breast cancers are often considered as low risk tumors in clinico-pathologic risk assessment and treatment guidelines. However, since the ability to metastasize is an early and inherent genetic property of breast cancer and consequently even small tumors can metastasize, identification of prognostic subgroups for patients with small tumors would help to optimize treatment strategies. In the present study the 70-gene prognosis signature (MammaPrint), validated as independent prognostic indicator for node-negative and positive patients, was used to assess prognosis for pT1 breast cancer. Methods: 965 tumor samples of women with pT1 breast cancer from 7 previously reported studies were analyzed and classified by MammaPrint as good or poor prognosis. 10-year distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS) was analyzed according to the 70-gene prognosis signature separately for pT1a/b (1–10mm) and pT1c (11–20mm) tumors. Results: Median follow-up was 7.1 years (range 0.2–25.2). 526 of 965 patients (55%) were classified as good prognosis and 439 (45%) as poor prognosis by the 70-gene signature. 562 patients (59%) received no adjuvant treatment, 19% received hormonal treatment only, 10% chemotherapy only and 12% both respectively. The 70-gene signature accurately predicted differences in 10-year DDFS (HR 2.7 [1.9–3.9], p&lt;0.01) and BCSS (HR 4.0 [2.6–6.3], p&lt;0.01) for all T1 tumors. Similar results were obtained by multivariate analysis for all patients, adjusted for known prognostic factors and adjuvant therapy, as well as for adjuvant untreated patients. At 10 years, for small pT1a/b tumors (n=140), DDFS was 93% vs. 78% for the good and poor prognosis groups (HR 3.9 [1.0–15.2], p=0.048), while in the T1c group (n=825) DDFS was 86% vs. 72% (HR 2.6 [1.8–4.0], p&lt;0.01). BCSS was 87% vs. 73% for the good and poor prognosis groups in the T1a/b group (HR 2.4 [0.8–7.7], p=0.128) and 92% vs. 72% (HR 4.4 [2.7–7.1], p&lt;0.01) in T1c tumors, respectively. Conclusions: The 70-gene signature is a strong and independent prognostic indicator also in small breast tumors. Patients with T1a/b or T1c tumors and a genomic high risk gene signature for developing distant metastases may be selected for additional adjuvant hormonal and chemotherapy. [Table: see text]

Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

BackgroundGene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival.MethodsTumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression.ResultsGene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes.ConclusionExpression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.