5-year Breast Cancer-specific Survival Research Articles

Abstract P6-07-04: Evaluation of Adjuvant! Online for primary operable grade 2 breast cancers with 10-year follow-up

Abstract Background: In primary operable breast cancers, Adjuvant!Online (AOL) uses demographics and clinic-pathological markers to predict the 10-year breast cancer specific survival (BCSS) with and without adjuvant systemic therapy. Grade 2 BC is a difficult group for adjuvant treatment decisions. We compared the observed with the AOL-estimated BCSS rate in our centre in consecutive women primary operated for a grade 2 BC. Patients and Methods: All patients with grade 2 primary operable breast cancer from UZL diagnosed between 1/1/2000 and 31/3/2002. After 10 years of follow-up, patients were evaluated for BCSS and dead from other cause. For each patient, the adjuvant! Online algorithm (version 8) was applied to predict BCSS taking the patients' adjuvant therapy into account. Adjuvant! Online was validated by assessing the calibration and discrimination. Discrimination was assessed by the area under the ROC curve. The expected BCSS rate was obtained by averaging the predicted probabilities of BCSS. Next, logistic calibration was performed by predicting observed BCSS within 10 years of follow-up with the odds of the predicted probability of BCSS (odds BCSS). In this analysis, the intercept should be 0 and the coefficient for odds BCSS 1 for perfect calibration of the predicted probabilities. A likelihood ratio test is used to test the null hypothesis of perfect calibration. Results: Six patients were lost to follow-up. The median age at diagnosis of the remaining 445 patients was 56 years (IQR 48 to 67 years, range 26 to 89 years). In 433/445 cases (97%), the prediction from AOL was available. The median AOL predicted probability for BCSS was 89.1% (IQR 83.2 to 94.6%, range 20.3 to 98.9%). The observed BCSS rate was 93.3% whereas the AOL-expected rate was 86.7%. The likelihood ratio test for perfect calibration was statistically significant (p < 0.0001), with an intercept of −1.55 (95% CI −2.33 to −0.84) and a coefficient for odds BCSS of 0.55 (95% CI 0.19 to 0.92). AOL strongly underestimated the probability of BCSS. The AUC was 0.65 (95% CI 0.53 to 0.76). For patients that did not die from BC within 10 years, the median estimated BCSS probability by AOL was 89.6% (IQR 83.5 to 94.6 %), whereas for patients that died from BC the median estimated probability was 83.9 % (IQR 77.9 to 94.5%). Conclusion: Although Adjuvant! Online achieved moderate discrimination between those that did and those that did not die from BC within 10 years FU, it clearly underestimated the probability of BCSS in our sample. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-04.

Abstract P6-07-40: Initial Neutrophil-to-Lymphocyte ratio in primary breast cancer patients: a simple and useful biomarker as prognostic factor

Abstract Background: Increasing neutrophil/lymphocyte ratios (NLR) on preoperative blood tests have been associated with worse survival of patients with colorectal, gastric, hepatocellular, pancreatic and lung cancer. However the utility of NLR to predict mortality in breast cancer patients has not been studied. The aim of our study was to determine whether the NLR is predictive of disease specific mortality in breast cancer and subtype-adjusted prognostic effect in breast cancer patients. Methods: We retrospectively identified all the patients with primary breast cancer diagnosed at Yonsei University Wonju Medical School between January 2000 and June 2011 who underwent primary surgery and completed all phase of their treatment. Breast cancer with infiltrating ductal histology was included and divided into 4 subtypes: Luminal A, Luminal B, Her2-enriched, and basal type. Each immunohistochemical characteristics are as followings: Luminal A: ER and/or PgR positive and negative Her2, Luminal B: ER and/or PgR positive with positive HER2, Her2-enriched: negative ER and PR with positive Her2, and triple negative as basal. Results: Patients with NLR≥2.5 showed significantly lower 5-year, 10-year breast cancer specific survival than patients with NLR<2.5. (5-year survival; 88.6% vs. 96.4%, p = 0.009, 10-year survival; 84.3% vs. 92.2%, p = 0.006). Cox proportional multivariate hazard model for cancer-specific mortality showed that patients with NLR≥2.5 has hazard ratio 4.71 with 95% confidence interval 1.77–12.53. Further analysis was done according to stratified patients' subgroup with intrinsic subtype. In Luminal A subtype, patients with NLR≥2.5 showed higher mortality rate(p = 0.014), while NLR≥2.5 failed to show statistical significance in the other subtype such as Luminal B, Her2 enriched, and triple negative subtype. Conclusion: Increased preoperative NLR is a significant prognostic factor in breast cancer specific survival and relevant in Luminal A subtype. This study shows that NLR could be a useful prognostic factor for breast cancer specific survival. And this study suggests that different factors could contribute as prognostic factor to each subtype, such as NLR was significant prognostic factor in Luminal A, while we couldn't find increased NLR is significant in other subtypes. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-40.

Multifocality and multicentricity in breast cancer and survival outcomes

The clinicopathological characteristics and the prognostic significance of multifocal (MF) and multicentric (MC) breast cancers are not well established. MF and MC were defined as more than one lesion in the same quadrant or in separate quadrants, respectively. The Kaplan-Meier product limit was used to calculate recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. Of 3924 patients, 942 (24%) had MF (n = 695) or MC (n = 247) disease. MF/MC disease was associated with higher T stages (T2: 26% versus 21.6%; T3: 7.4% versus 2.3%, P < 0.001), grade 3 disease (44% versus 38.2%, P < 0.001), lymphovascular invasion (26.2% versus 19.3%, P < 0.001), and lymph node metastases (43.1% versus 27.3%, P < 0.001). MC, but not MF, breast cancers were associated with a worse 5-year RFS (90% versus 95%, P = 0.02) and BCSS (95% versus 97%, P = 0.01). Multivariate analysis shows that MF or MC did not have an independent impact on RFS, BCSS, or OS. MF/MC breast cancers were associated with poor prognostic factors, but were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.

Factors affecting 5- and 10-year survival of women with breast cancer: An analysis based on a public general hospital in Barcelona

BackgroundData from a long-established hospital-based cancer registry were used to analyse the relationship between clinical and organisational factors and disease-specific survival among women with primary breast cancer. Methods2023 women with incident invasive breast cancer diagnosed from 1992 to 2005 were identified through the Hospital del Mar Cancer Registry (Barcelona, Spain). Patients were followed until December 2008. One-, 5- and 10-year disease-specific survival rates were estimated. Kaplan–Meier and Cox regression models were used to analyse death from breast cancer. ResultsAt diagnosis 70.2% of tumours were in stages I–II. During follow-up 705 deaths occurred, 58.4% specifically due to breast cancer. Five- and 10-year breast cancer specific survival rates were 83.3% and 73.7%, respectively (stage I, 97.1% and 94.0%; stage II, 88.0% and 79.4%; stage III, 70.1% and 46.3%, and stage IV, 24.5% and 6.1%, respectively). The 5-year disease-specific survival rate increased from 73.5% in 1992–1995 to 86.4% in 2001–2005 (log rank, p<0.001). Multivariate analyses showed that prognosis was less favourable for women diagnosed between 1992 and 1995, for those whose route to diagnosis was not the screening programme, women aged ≥70 years, with stage IV tumours, with high grade lesions, and for women who received only palliative or symptomatic treatment. Adjusting for prognostic factors, surgeon's experience did not significantly appeared to affect survival of operated women. ConclusionsIn this centre survival from breast cancer improved markedly from 1992 to 2005. Breast cancer prognosis was influenced by both clinical and organisational variables. The quantification of the role of such factors affords valuable knowledge to improve cancer care in settings similar to the study hospital.

Clinical Implications of CD44+/CD24− Tumor Cell Ratio in Breast Cancer

To investigate the association of the CD44+/CD24- cancer stem cell (CSC) ratio with clinicopathologic features and its prognostic value in breast cancer. The CD44+/CD24- CSC ratio was determined in formalin-fixed, paraffin-embedded breast cancer tissues from 1350 breast cancer patients by double immunofluorescence staining. The Cox regression analysis was performed to evaluate whether the CD44+/CD24- CSC ratio is an independent prognostic factor. The Kaplan-Meier survival analysis was conducted to determine the association of the CD44+/CD24- CSC ratio with cancer-specific survival. The mean average CSC ratio in clinical specimens was 8.06% (range from 1.02% to 37.54%). The CD44+/CD24- CSC ratio, together with histological grade, molecular type, and clinical stage, was independent prognostic factors of breast cancer. The CD44+/CD24- CSC ratio was significantly correlated with estrogen receptor (ER), progesterone receptor (PR), and Ki67, but not the Her-2 and P53 status. Furthermore, the CD44+/CD24- CSC ratio was significantly associated with 5-year breast cancer-specific survival in 1242 cases (88.97% vs. 75.76% vs.52.11% for ≤ 5%, 5%-10% and >10% CSC ratio cases, respectively, p=0.001). The linear regression analysis showed that the CSC ratio was borderlinely correlated with the N stage related (R=0.397 p=0.06), and significantly correlated with distant recurrence (R=0.487, p=0.01) in 1350 specimens. After the survival analysis, the 5-year distant recurrence rates were (57/435 [13.10%] vs. 159/594 [26.77%] vs. 114/213 [53.52%] for ≤ 5%, 5%-10%, and >10% CSC ratio cases, p=0.001). The CSC ratio was an independent prognostic factor for breast cancer as well as a potential predictive marker for chemotherapy in breast cancer.

Long-term (37 years) clinical outcome of older women with early operable primary breast cancer managed in a dedicated clinic

A dedicated clinic for older women with early primary breast cancer, established in 1973, has recently evolved into a combined surgical/oncology facility. This study aimed to compare the clinical outcome across these periods. From 1973 to 2010, 1758 women were managed. Analysis was carried out based on retrospective review and continued update of patient records. In the recent decade, 56.3% had surgery, followed by primary endocrine therapy (PET; 41.1%) and primary radiotherapy (1.5%). Before 1999, 42.8%, 55.6% and 1% of patients had surgery, PET and primary radiotherapy, respectively. The use of adjuvant endocrine therapy and radiotherapy has increased from 33.6% to 54.9% and 5.8% to 34.6%, respectively. A significant improvement was seen in the annual rates of local (2.2% versus 0.5%, P < 0.001), regional (1.8% versus 0.4%, P < 0.001) and distant (2.9% versus 1.9%, P = 0.002) recurrences. Similarly, the 5-year breast cancer-specific and overall survival rates showed improvement [81% versus 91% (P < 0.001) and 56% versus 71% (P < 0.001), respectively]. In the recent decade, while surgery became the predominant treatment, a significant proportion of patients had non-operative therapies, selection of which was based on multidisciplinary assessment in the clinic. This management approach appears to produce excellent clinical outcome, which is significantly better than that in earlier period.

Impact of surgery and radiation of the primary among women with de novo stage IV breast cancer.

1032 Background: The aim of this retrospective study was to determine the impact of surgery(S) and radiation(R) therapy to the primary tumor among patients (pts) with stage IV denovo breast cancer. Methods: The SEER registry was used to identify pts with denovo stageIV breast cancer diagnosed between 1988 and 2008. Pts were divided into 4 groups based on type of treatment to primary tumor: both S+R, S alone, R alone, or no treatment of primary (no S/R). Breast cancer specific survival (BCS) was calculated from the date of diagnosis of breast cancer to the date of death from breast cancer or last follow up. Survival outcomes were estimated by the Kaplan-Meier method, and Cox models were fit to determine the association between treatment of primary and survival after adjusting for potential confounders (e.g age, grade, hormone receptor and race). Results: 25903 pts were identified; 4640 (17.9%) S+R, 6556 (25.3%) S, 4467 (17.2%) R, and 10240 (39.5%) no S/R. 1183 (4.6%) had surgery to sites other than the primary. Median age was 63 years. Median follow-up was 14 months. Median BCS was 23 months. Median BCS among pts who underwent S+R, S, R and no S/R was 36 months, 31 months, 18 months and 15 months respectively (p&lt;0.0001). Among pts who underwent S+R, median BCS among pts who did and did not have surgery to sites other than primary was 50 months and 41 months respectively (p=0.029). Of the pts treated with S+R 10-year BCS was 18%. In the multivariable model compared to women who were in the no S/R group those who underwent S (HR= 0.59, 95%CI 0.55- 0.62,p&lt;0.0001) and S+R (HR=0.51, 95%CI 0.47-0.55,p&lt;0.0001) had decreased risk of death from breast cancer and those who underwent R (HR=1.13, 95% CI 1.04-1.21, p=0.002) had an increased risk of death from breast cancer. Pts who had surgery to sites other than the primary tumor had decreased risk of death from breast cancer compared to those who did not (HR=0.80, 95%CI 0.72-0.89,p&lt;0.0001). Conclusions: Our results indicate that S+R of the primary breast tumor among pts with denovo stage IV breast cancer maybe associated with a decreased risk of death from breast cancer. A select subgroup of pts who undergo S+R may also benefit from surgery to sites other than the primary which may afford them maximum survival advantage.

Breast cancer multifocality-multicentricity and survival outcomes.

1104 Background: Studies have consistently shown a correlation between multifocal (MF) and multicentric (MC) breast cancers and the rate and extent of lymph node metastases, but the literature is divided on whether there is a corresponding impact on survival outcomes. In the absence of compelling evidence to dictate otherwise, the convention according to current TNM staging guidelines has been to stage and treat MF and MC cancers according to the diameter of the largest lesions, without taking other foci of disease into consideration. We evaluated a large single institution cohort of MF and MC breast cancers to determine their frequency, clinico-pathological characteristics and effect on survival outcomes. Methods: MF and MC were defined pathologically as more than one lesion in the same quadrant and more than one lesion in separate quadrants, respectively. Patients were categorized by presence or absence of MF or MC disease. Kaplan-Meier product limit method was used to calculate relapse-free survival (RFS), breast cancer-specific survival (BCSS) and overall survival (OS). Cox proportional hazards models were fit to determine independent associations of MF/MC disease with survival outcomes. Results: Out of 3924 patients, 942 (24%) had MF (n=695) or MC (n=247) disease. MF and MC disease was associated with higher T-stages (T2 26% vs. 21.6%; T3 7.4% vs. 2.3%, P&lt;0.001), higher nuclear grade (grade 3 44% vs. 38.2%, P&lt;0.001), lymphovascular invasion (26.2% vs. 19.3%, P&lt;0.001) and lymph node metastases (43.1% vs. 27.3%, P&lt;0.001). After a median follow up of 51 months, MC but not MF breast cancers were associated with significantly worse 5-year RFS (90% vs. 95%, P=0.02) and BCSS (95% vs. 97%, P=0.01), and a trend towards worse 5-year OS (92% vs. 93%, P=0.08). After controlling for other risk factors, multifocality and multicentricity did not have an independent impact on RFS, BCSS or OS. This was true for the subset of T1N0 breast cancers as well. Conclusions: MF and MC breast cancers occurred in 24% of the cases and were associated with poor prognostic factors, but they were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T-stage.

Aurora kinase A outperforms Ki67 as a prognostic marker in ER-positive breast cancer

Background:Proliferation has emerged as a major prognostic factor in luminal breast cancer. The immunohistochemical (IHC) proliferation marker Ki67 has been most extensively investigated but has not gained widespread clinical acceptance.Methods:We have conducted a head-to-head comparison of a panel of proliferation markers, including Ki67. Our aim was to establish the marker of the greatest prognostic utility. Tumour samples from 3093 women with breast cancer were constructed as tissue microarrays. We used IHC to detect expression of mini-chromosome maintenance protein 2, Ki67, aurora kinase A (AURKA), polo-like kinase 1, geminin and phospho-histone H3. We used a Cox proportional-hazards model to investigate the association with 10-year breast cancer-specific survival (BCSS). Missing values were resolved using multiple imputation.Results:The prognostic significance of proliferation was limited to oestrogen receptor (ER)-positive breast cancer. Aurora kinase A emerged as the marker of the greatest prognostic significance in a multivariate model adjusted for the standard clinical and molecular covariates (hazard ratio 1.3; 95% confidence interval 1.1–1.5; P=0.005), outperforming all other markers including Ki67.Conclusion:Aurora kinase A outperforms other proliferation markers as an independent predictor of BCSS in ER-positive breast cancer. It has the potential for use in routine clinical practice.

The Impact of Diabetes Mellitus on Prognosis of Early Breast Cancer in Asia

Diabetes mellitus (DM) has been implicated in influencing the survival duration of patients with breast cancer. However, less is known about the impact of DM and other comorbidities on the breast cancer-specific survival (BCS) and overall survival (OS) outcomes of Asian patients with early-stage breast cancer. The characteristics of female patients with newly diagnosed, early-stage breast cancer were collected from the Taiwan Cancer Registry database for 2003-2004. DM status and other comorbidities were retrieved from Taiwan's National Health Insurance database. The BCS and OS times of patients according to DM status were estimated via the Kaplan-Meier method. Cox's proportional hazard model was used to estimate adjusted hazard ratios (HRs) for the effects of DM, comorbidities, and other risk factors on mortality. In total, 4,390 patients were identified and 341 (7.7%) presented with DM. The 5-year BCS and OS rates were significantly greater in DM patients than in non-DM patients (BCS, 85% versus 91%; OS, 79% versus 90%). Furthermore, after adjusting for clinicopathologic variables and comorbidities, DM remained an independent predictor of shorter BCS (adjusted HR, 1.53) and OS (adjusted HR, 1.71) times. Subgroup analyses also demonstrated a consistent prognostic influence of DM across different groups. In Asian patients with early-stage breast cancer, DM is an independent predictor of lower BCS and OS rates, even after adjusting for other comorbidities. The integration of DM care as part of the continuum of care for early-stage breast cancer should be emphasized.

Effect of Community Population Size on Breast Cancer Screening, Stage Distribution, Treatment Use and Outcomes

Residents of rural communities have decreased access to cancer screening and treatments compared to urban residents, though use of resources and patient outcomes have not been assessed with a comprehensive population-based analysis. The objectives of this study were to investigate whether breast cancer screening and treatments were utilized less frequently in rural BC and whether this translated into differences in outcomes. All patients diagnosed with breast cancer in British Columbia (BC) during 2002 were identified from the Cancer Registry and linked to the Screening Mammography database. Patient demographics, pathology, stage, treatments, mammography use and death data were abstracted. Patients were categorized as residing in large, small and rural local health authorities (LHAs) using Canadian census information. Use of resources and outcomes were compared across these LHA size categories. We hypothesized that mastectomy rates (instead of breast-conserving surgery) would be higher in rural areas, since breast conservation is standardly accompanied by adjuvant radiotherapy, which has limited availability in rural BC. In contrast we hypothesized that cancer screening and systemic therapy use would be similar, as they are more widely dispersed across BC. Exploratory analyses were performed to assess whether disparities in screening and treatment utilization translated into differences in survival. 2,869 breast cancer patients were included in our study. Patients from rural communities presented with more advanced disease (p=0.01). On multivariable analysis, patients from rural, compared to urban, LHAs were less likely to be screening mammography attendees (OR=0.62; p<0.001). Women from rural communities were less likely to undergo breast-conserving surgery (multivariable OR=0.47; p<0.001). There was no significant difference in use of chemotherapy (p=0.54) or hormonal therapy (p=0.36). The 5-year breast cancer-specific survival for large, small and rural LHAs was 90%, 88% and 86%, respectively (p=0.08), while overall survival was 84%, 81% and 77%, respectively (p=0.01). On multivariable analysis with 7.4 years of median follow-up, neither breast cancer-specific survival (HR=1.16; 0.76-1.76; p=0.49) nor overall survival (HR=1.25; 0.92-1.70; p=0.16) was significantly worse for patients from rural compared to large LHAs. There was a significant difference in screening mammography use, stage distribution and loco-regional treatments use by population size of LHA. After controlling for differences in patient and tumour factors by LHA, survival was not significantly different.

Effect of Community Population Size on Breast Cancer Screening, Stage Distribution, Treatment Use and Outcomes

Residents of rural communities have decreased access to cancer screening and treatments compared to urban residents, though use of resources and patient outcomes have not been assessed with a comprehensive population-based analysis. The objectives of this study were to investigate whether breast cancer screening and treatments were utilized less frequently in rural BC and whether this translated into differences in outcomes. All patients diagnosed with breast cancer in British Columbia (BC) during 2002 were identified from the Cancer Registry and linked to the Screening Mammography database. Patient demographics, pathology, stage, treatments, mammography use and death data were abstracted. Patients were categorized as residing in large, small and rural local health authorities (LHAs) using Canadian census information. Use of resources and outcomes were compared across these LHA size categories. We hypothesized that mastectomy rates (instead of breast-conserving surgery) would be higher in rural areas, since breast conservation is standardly accompanied by adjuvant radiotherapy, which has limited availability in rural BC. In contrast we hypothesized that cancer screening and systemic therapy use would be similar, as they are more widely dispersed across BC. Exploratory analyses were performed to assess whether disparities in screening and treatment utilization translated into differences in survival. 2,869 breast cancer patients were included in our study. Patients from rural communities presented with more advanced disease (p=0.01). On multivariable analysis, patients from rural, compared to urban, LHAs were less likely to be screening mammography attendees (OR=0.62; p<0.001). Women from rural communities were less likely to undergo breast-conserving surgery (multivariable OR=0.47; p<0.001). There was no significant difference in use of chemotherapy (p=0.54) or hormonal therapy (p=0.36). The 5-year breast cancer-specific survival for large, small and rural LHAs was 90%, 88% and 86%, respectively (p=0.08), while overall survival was 84%, 81% and 77%, respectively (p=0.01). On multivariable analysis with 7.4 years of median follow-up, neither breast cancer-specific survival (HR=1.16; 0.76–1.76; p=0.49) nor overall survival (HR=1.25; 0.92-1.70; p=0.16) was significantly worse for patients from rural compared to large LHAs. There was a significant difference in screening mammography use, stage distribution and loco-regional treatments use by population size of LHA. After controlling for differences in patient and tumour factors by LHA, survival was not significantly different.

Utilization of fluorescence in situ hybridization with cytokeratin discriminators in TOP2A assessment of chemotherapy-treated patients with breast cancer

Tumor biomarkers increasingly provide information for predicting outcomes with chemotherapeutic regimens (personalized medicine). Topo2A is a DNA helicase targeted by anthracyclines, cytotoxic therapeutics used in both adjuvant and palliative treatments of breast cancer. TOP2A gene amplification/deletion is implicated in response to anthracycline-based chemotherapy. We describe an approach for analyzing formalin-fixed, paraffin-embedded breast tumors on tissue microarrays with TOP2A fluorescence in situ hybridization coupled with cytokeratin immunofluorescence to target tumor cells. Stained tissue from patient specimens was imaged and analyzed using Metafer/Metacyte (Metasystems, Waltham, MA, USA), including customized image classifiers. TOP2A/CEN17 ratios of 2.0 or greater (amplified) and 0.8 or less (deleted) were observed for 10.0% and 6.1% of the patients, respectively. Patient outcomes for adjuvant chemotherapy (cyclophosphamide-epirubicin-fluorouracil, cyclophosphamide-methotrexate-fluorouracil, no chemotherapy) were evaluated. No statistical significance was achieved for clinical end points regarding TOP2A status in anthracycline-treated patients. However, patients with TOP2A aberrations receiving methotrexate-based therapy exhibited a significant decrease in 5-year distant disease-free survival and breast cancer-specific overall survival, especially for patients with TOP2A deletions (disease-free survival: hazard ratio, 5.31 [P = .001], and breast cancer-specific overall survival: hazard ratio, 6.45 [P ≤ .001]). No significant differences were seen in patients included in the no-chemotherapy group. Topo2A protein levels were assessed by immunohistochemistry with no correlative statistical relevance to immunofluorescence/fluorescence in situ hybridization-based prognosis for cyclophosphamide-epirubicin-fluorouracil or cyclophosphamide-methotrexate-fluorouracil groups. Interestingly, aberrant (under)expressing patients in the no-chemotherapy group exhibited better 5-year distant disease-free survival (hazard ratio, 0.39; P = .004), trending toward more favorable breast cancer-specific overall survival (hazard ratio, 0.61; P = .11). Our results indicate a strategy by which fluorescence in situ hybridization scoring targeted to cytokeratin-positive tumor cells may provide a tool for added precision and efficiency in TOP2A evaluation from tumor tissue.

P2-12-22: A Prognostic Index Composed of Progesterone Receptor Status, Tumour Size and S-phase Fraction, Predicts Survival in Node-Negative Breast Cancer Patients in a Large Multicentre Prospective Cohort Study.

Abstract Background The importance of the added prognostic value of proliferation, either single factors such as Ki67 or flow cytometric S-phase fraction (SPF), or as the main common denominator in the majority of gene expression profiles, has been highlighted over the last years in node-negative breast cancer. There are however few published prospective studies. In an earlier retrospective study on node-negative breast cancer from our group, a prognostic index consisting of PR status, tumour size and a proliferation factor, SPF, identified one third of the patients as high risk, with a fourfold increased risk of distant recurrence. The present study was set up to validate this index in a large prospective multicenter cohort study with long term follow-up. Material and Methods: 596 patients from 3 regions in Sweden were between 1991–1995 included in the study. Inclusion criteria were: 10mm≤tumour size≤50mm, node-negativity, ≥5 lymph nodes removed, age &amp;lt;60 years, and radical surgery. Patients with bilateral breast cancer or previous malignancy were excluded. Prospective analyses of ER, PR, and flow cytometric SPF were performed. High- risk was defined as 2 or more of the following: 1. size &amp;gt;20mm 2. PR- (in the absence of PR status, ER-) and 3. high SPF (in the absence of SPF, Bloom Richardson grade 3). 82% of the patients received no adjuvant medical treatment. Cox proportional hazards regression, stratified for centre, was used to model the impact of the index on breast cancer specific survival (BCSS). Median follow-up was 16 years for the 452 patients alive at last follow-up. Analyses were done after 5 and 10 years follow-up, during which 42 and 95 patients, respectively, died of breast cancer. Results: 31% of the patients were identified as high-risk. In univariate analysis, the index was prognostic for BCSS after 5 years (HR 5.1, 95%CI: 2.7−9.8,) as well as 10 years (HR 2.2, 95%CI: 1.5−3.4). The prognostic impact remained significant after adjustment for adjuvant medical treatment and age. The 5- and 10-year BCSS (95%CI) was 97% (94-98) and 87% (83-90) for low risk patients, compared with 85% (79-89) and 76% (69-81) for high risk patients. In the group with no risk factors (n=218 ), no patient died of breast cancer during the first 5 years. Proliferation was the strongest factor for BCSS followed by PR and tumour size, both in uni- and multivariate analyses. In multivariate analysis, adjusted for adjuvant treatment and age, the HR for proliferation was 7.5 (95%CI: 3.2-18) after 5 years and 2.5 (95%CI: 1.6−4.0) after 10 years. Discussion: This large prospective multicenter cohort study validates the results from an earlier retrospective study, that a prognostic index consisting of PR status, tumour size and a proliferation factor, SPF, reliably identifies one third of the node-negative patients with a high risk of relapse. The index also identifies an extreme low risk group; patients with no risk factors, with 100% 5-year survival. This group could be spared adjuvant medical treatment, especially chemotherapy. Taken together, this index may be clinically helpful for prognostic considerations and for selection of adjuvant treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-22.

Increased gene copy number of KIT and VEGFR2 at 4q12 in primary breast cancer is related to an aggressive phenotype and impaired prognosis

Triple-negative breast cancer (TNBC) is associated with poor prognosis and no targeted treatments are available for TNBC. Drugs inhibiting tyrosine kinases, such as vascular endothelial growth factor receptor 2 (VEGFR2) and KIT, have shown some promising results for patients with TNBC. The aim of the study was to investigate whether gains and/or amplifications of VEGFR2 and KIT, located at 4q12, occur in TNBC. Fluorescence in situ hybridization (FISH) was used to quantify gene copy numbers of VEGFR2 and KIT in 83 primary human breast cancers including 31 TNBCs. Gains were defined as ≥ 4 gene copies in >40% of the cancer cells, whereas amplification was defined as CEP >2 in more than 10% of the cancer cells. A tumor was considered FISH positive for KIT and/or VEGFR2 if it displayed copy number gain and/or amplification. Ten (32%) of the TNBCs were VEGFR2 FISH positive and nine (29%) were KIT FISH positive, whereas non-TNBCs were FISH positive for VEGFR2 and KIT in nine (18%) cases for both genes, but no significant difference between TNBCs and non-TNBCs was found. FISH positivity for VEGFR2 and KIT was significantly correlated (χ(2) test, P < 0.001), and significantly related to ER negativity and high Nottingham histological grade (NHG). A significantly worse 5-year breast cancer specific survival (BCSS) was seen for FISH positive cases. Increased copy number of VEGFR2 and KIT thus has the potential of functioning as a novel predictive biomarker for selected targeted therapy particularly in the difficult-to-treat TNBC patient category.

Variants on the promoter region of PTEN affect breast cancer progression and patient survival

IntroductionThe PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.MethodsWe screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.ResultsAll three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.ConclusionsInherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.

A Case-Match Study Comparing Unilateral With Synchronous Bilateral Breast Cancer Outcomes

There is controversy about whether patients with synchronous bilateral breast cancer (SBBC) have similar or worse outcomes compared with patients with unilateral breast cancer. The purpose of this study was to determine whether survival outcomes for patients with SBBC can be estimated from the characteristics of their individual cancers. Patients had invasive breast cancer, without metastases or inflammatory disease, diagnosed in British Columbia between 1989 and 2000. There were 207 cases with SBBC (diagnosed ≤ 2 months apart) and 15,497 with unilateral breast cancer. By using 10-year breast cancer-specific survival (BCSS) estimates, the higher-risk cancer of each SBBC case was determined and matched with three breast cancers from the unilateral cohort to select 621 high-risk matches. The priority sequence of matching the prognostic and predictive variables was positive lymph node number, primary tumor size, age, grade, lymphovascular invasion, estrogen receptor status, local therapy used, margin status, treating clinic, diagnosis year, and type of systemic therapy used. With a median follow-up of 10.2 years, the overall 10-year BCSS was significantly higher for the unilateral cohort (81%; 95% CI, 81% to 82%) than for the SBBC cases (71%; 95% CI, 63% to 77%). The SBBC cases had significantly higher mean age and stage at presentation. The 10-year BCSS was 74% (95% CI, 69% to 77%) for the high-risk matches. BCSS was not significantly different between the SBBC cases and their high-risk matches.

Impact of internal mammary node inclusion in the radiation treatment volume on the outcomes of patients with breast cancer treated with locoregional radiation after six years of follow-up.

81 Background: There is ongoing controversy about radiotherapy (RT) to internal mammary nodes (IMNs). Proponents of IMN RT cite the survival benefit seen in postmastectomy RT trials that included IMNs. However, others point out that benefit cannot be definitively attributed to IMN inclusion, as other lymph node regions were included in the RT arms. The issue is important, as IMN RT potentially increases cardiac and respiratory morbidity. Methods: 2,413 women referred to a provincial RT program with newly diagnosed node positive, or T3/4N0 non-M1 invasive breast cancer, treated with a complete course of locoregional RT from 2001 to 2006, were retrospectively identified in a provincial database. IMN RT inclusion versus exclusion was determined through review of patient charts and RT treatment plans. Breast cancer-specific survival (BCSS), relapse-free survival (RFS), and overall survival (OS) were compared between the two groups using univariate and multivariable analyses. Results: Analyses were performed at a median follow-up of 6.2 years. 41.4% of the subjects received IMN RT. The 5-year BCSS for the IMN inclusion and exclusion group was 84.8% versus 82.9%, respectively (HR 0.93 [95% CI 0.76, 1.14]; p=.51); the 5-year RFS was 87.4% versus 86.9% (HR 0.993 [0.83, 1.19]; p=0.94); and the 5-year OS was 84.8% versus 82.9% (HR 0.84 [0.70, 1.01]; p=0.06). After controlling for potentially confounding variables, there was no significant difference in BCSS (HR 0.96 [0.78, 1.18], p=0.88), RFS (HR 1.02 [0.84, 1.22], p=0.87), or OS (HR 0.91 [0.76, 1.10]; p=0.35). Conclusions: After a median follow-up of 6.2 years, this population-based study shows no benefit from including IMNs in the locoregional RT volume after adjusting for other prognostic and treatment variables.

A population-based validation of the prognostic model PREDICT for early breast cancer

Introduction Predict ( www.predict.nhs.uk) is a prognostication and treatment benefit tool developed using UK cancer registry data. The aim of this study was to compare the 10-year survival estimates from Predict with observed 10-year outcome from a British Columbia dataset and to compare the estimates with those generated by Adjuvant! ( www.adjuvantonline.com). Method The analysis was based on data from 3140 patients with early invasive breast cancer diagnosed in British Columbia, Canada, from 1989–1993. Demographic, pathologic, staging and treatment data were used to predict 10-year overall survival (OS) and breast cancer specific survival (BCSS) using Adjuvant! and Predict models. Predicted outcomes from both models were then compared with observed outcomes. Results Calibration of both models was excellent. The difference in total number of deaths estimated by Predict was 4.1 percent of observed compared to 0.7 percent for Adjuvant!. The total number of breast cancer specific deaths estimated by Predict was 3.4 percent of observed compared to 6.7 percent for Adjuvant! Both models also discriminate well with similar AUC for Predict and Adjuvant! respectively for both OS (0.709 vs 0.712) and BCSS (0.723 vs 0.727). Neither model performed well in women aged 20–35. Conclusion In summary Predict provided accurate overall and breast cancer specific survival estimates in the British Columbia dataset that are comparable with outcome estimates from Adjuvant! Both models appear well calibrated with similar model discrimination. This study provides further validation of Predict as an effective predictive tool following surgery for invasive breast cancer.

In Patients Younger Than Age 55 Years With Lymph Node–Negative Breast Cancer, Proliferation by Mitotic Activity Index Is Prognostically Superior to Adjuvant!

In breast cancer, different tools are used for prognostication and adjuvant systemic therapy selection. We compared the accuracy of the online program Adjuvant!, the Norwegian Breast Cancer Group (NBCG) guidelines, and the proliferation factor mitotic activity index (MAI) in patients with lymph node (LN) -negative disease (pN0). Adjuvant! and MAI thresholds were set to 90% to 95% breast cancer-specific survival (BCSS) rates. These thresholds were 95% for Adjuvant!, 3 for MAI, and as follows for NBCG: pT1 grade 1 + pT1a-b grade 2 to 3; all pN0M0 and estrogen receptor/progesterone receptor positive versus all others. In 516 patients younger than age 55 years (T1-3N0M0) without adjuvant systemic therapy, univariable and multivariable 10-year BCSS rates were estimated. Median follow-up time was 118 months. The concordance between MAI and Adjuvant! or NBCG was fair (κ = 0.35 and κ = 0.29, respectively). Adjuvant!, NBCG, and MAI were all prognostically significant (P ≤ .001). In the univariable analysis, the 10-year BCSS of MAI less than 3 versus ≥ 3 was 95% v 71%, respectively, with a hazard ratio of 7.0. In multivariable analysis, MAI was superior to Adjuvant! and NBCG. The 10-year survival of Adjuvant! ≥ 95% versus less than 95% was 91% v 74%, respectively, but stratification by MAI identified subgroups with different prognosis. Similar results occurred for NBCG and MAI. Adjuvant! and NBCG were not prognostic to each other. MAI is superior to Adjuvant! and NBCG in prognostication of patients with LN-negative breast cancer younger than age 55 years.