Breast Cancer-related Survival Research Articles

Survival Impact of Long-Term Tramadol Use on Breast Cancer for Patients with Chronic Pain: A Propensity Score-Matched Population-Based Cohort Study.

Purpose: The impact of tramadol analgesic use before breast cancer diagnosis on survival in patients with chronic pain is unclear. Therefore, we designed a propensity score-matched population-based cohort study to compare the breast cancer-related survival of patients with chronic pain who received long-term tramadol analgesic treatment with that of those who did not receive such treatment. Patients and Methods: We included patients with chronic pain and categorized them into two groups according to their analgesic use, comparing their breast cancer-related survival; patients with breast cancer and chronic pain who were prescribed ≥180 defined daily doses (DDDs) of tramadol analgesics per year >3 months before breast cancer diagnosis comprised the case group, and those who were prescribed non-tramadol analgesics before breast cancer diagnosis comprised the control group. Patients in both groups were matched at a ratio of 1:5. Results: The matching process yielded a final cohort of 624 patients (104 and 520 in the case and control groups, respectively) who were eligible for further analysis. According to both univariate and multivariate Cox regression analyses, the adjusted hazard ratio for all-cause death in the case group compared with in the control group was 3.45 (95% confidence interval = 2.36–5.04; p < 0.001). Conclusion: Long-term tramadol analgesic use prior to breast cancer diagnosis might be associated with poor overall survival in patients with chronic pain compared with such patients that did not receive long-term tramadol analgesic treatment.

Prognostic Value of the TP53 Mutation Location in Metastatic Breast Cancer as Detected by Next-Generation Sequencing.

PurposeThe status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site.Patients and MethodsBlood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples.ResultsAmong the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5–8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P<0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P<0.001, respectively). TP53-mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant.ConclusionTP53-mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2– and TNBC cohorts. Of TP53-mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.

Analysis of the tumor characteristics in young age breast cancer patients using collaborative stage data of the Korea Central Cancer Registry.

This study aimed to evaluate tumor characteristics in young age (20-39years old) breast cancer (YABC) patients in Korea. We identified 10,897 breast cancer patients from 2010 to 2015. The data were collected through 10% systematic sampling of the Korea National Cancer Incidence Database (KNCI DB). Tumor size, lymph node status, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were collected according to the Collaborative Stage version 2 (CSv2) Data Collection System. Of the 10,897 patients, 1245 (11.4%) were YABC patients. They were found to have larger tumors (T2: 41.6% in 20-39 age group vs 36.4% in 40-49 age group vs 36.5% in 50-59 age group vs 38.4% in ≥ 60 age group; T3: 10.1% vs 7.3% vs 6.5% vs 6.2%, P < .0001), greater rates of lymph node involvement (41.2% vs 32.7% vs 35.7% vs 32.5%, P < .0001), higher tumor grade (High grade: 26.8% vs 19.4% vs 23.5% vs 22.1%, P < .0001), and a larger proportion of triple-negative subtype (18.2% vs 11.0% vs 12.2% vs 13.5%, P < .0001). Compared to the 40-49 age group, breast cancer-related survival (BCRS) rates were worse (91.74% vs 95.04%, P < .0001), and the characteristics of YABC patients were associated with higher risk of death from breast cancer. YABC patients have more aggressive tumor characteristics and worse survival rates. Therefore, we need to identify high-risk groups among YABC patients and support active surveillance in them. These findings from a national cohort provide important information for establishing a national cancer care strategy to manage YABC patients.

Abstract PS1-07: Elderly breast cancer patients benefit from surgery according to guidelines

Abstract Background: With a globally increasing population of otherwise healthy people above 70 years, more knowledge on treatment and prognosis of breast cancer patients in this group is needed. In Denmark, the Danish Breast Cancer Group describes national treatment guidelines for diagnostic work-up and surgical and oncological treatment of all patients with primary invasive breast cancer with no upper age limit. Still, many patients ≥70 years, regardless of comorbidity, do not adhere to treatment guidelines, often receiving less imaging and less treatment than recommended. The aims of the present study were to examine, among patients ≥70 years with primary invasive breast cancer, whether endocrine treatment only, resulted in an inferior breast cancer related survival compared to standard surgical and oncological treatment, to examine whether patients treated with breast conserving surgery (BCS) with no preoperative imaging had a higher risk of local recurrence than patients receiving preoperative imaging, and finally to examine whether clinically node negative patients had a higher risk of regional recurrence if they did not receive axillary staging. Methods: All women, ≥70 years, diagnosed with primary invasive breast cancer and treated at the Department of Breast Surgery at Herlev Hospital, Denmark, from 2000-2007 were included. Patients were prospectively registered in a hospital-based database. Differences in standardized mortality ratios (SMR) between patients treated by surgery, endocrine therapy only, or endocrine therapy followed by surgery were estimated by Poisson regression and evaluated by rate ratios. Differences in local recurrence between patients with and without preoperative imaging before BCS, and in regional recurrence between surgically treated patients with and without a sentinel lymph node biopsy, with axillary clearance in case of a positive sentinel node, excluding clinically node positive patients directly treated with an axillary clearance, were estimated by Cause Specific Hazards Models and evaluated by cause specific hazard ratios (HR). Adjustments were made for age, comorbidity, adjuvant radiotherapy, tumor size, time since diagnosis, and time period. Results: In total 1,142 patients were included in the study. The median age was 77 years. For overall mortality, median follow-up was 7.80 years, with 795 (69.6%) dying during follow-up, and for recurrence 6.25 years. 52 were registered with local recurrence and 39 with regional recurrence. Patients who received only endocrine therapy had a significantly higher SMR than patients treated with primary surgery (adj. RR=2.57; 95% CI: 2.01-3.30), while patients who received endocrine therapy followed by later surgery did not (RR=1.23; 95% CI: 0.91-1.66). 253 out of 580 patients with BCS (43.6%) did not have preoperative imaging. Patients without imaging did not have a higher risk of local recurrence compared to patients with preoperative imaging (adj. HR=1.14; 95% CI: 0.36-3.67). 13 out of 197 surgically treated patients without axillary surgery (6,8%) had regional recurrence, while only 7 out of 428 patients (1.6%) with axillary staging by sentinel node biopsy had regional recurrence. This difference was significant (adj. HR 4.68 95% CI=1.53-14.37). Conclusions: In the present study we have shown that women ≥70 years, diagnosed with primary invasive breast cancer, have a higher mortality if they are not surgically treated, and they have a higher risk of regional recurrence if they are not offered axillary staging. The study emphasizes that unless elderly patients have comorbidity contraindicating surgery, they should be treated according to guidelines. Citation Format: Mathias Kvist Mejdahl, Mette Haulund Christensen, Birgitte Paaschburg Nielsen, Tove HolstFiltenborg Tvedskov. Elderly breast cancer patients benefit from surgery according to guidelines [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-07.

Abstract P1-10-07: The presence of ductal carcinoma in situ in core needle biopsy and microcalcifications on mammography in TNBC is associated with a lower pCR and worse long term outcome

Abstract Purpose Predictors for pathological Complete Response (pCR) in TNBC are very important given pCR is considered a surrogate marker for breast cancer-related survival. Associated DCIS in TNBC (accom-DCIS) as well as presence of microcalcifications on initial mammography (micro-MG) have been correlated with Androgen Receptor positive TNBC, known to achieve lower pCR rates. We aim to investigate the predictive impact of accom-DCIS and micro-MG on pCR. We also validated known clinico-pathological predictors for pCR. Long term outcome was analyzed for pCR and accom-DCIS. Methods A retrospective cohort study (diagnosed 1/1/2000 - 31/12/2017) of prospectively registered consecutively treated TNBC patients was performed. TNBC was defined as IHC-ER&amp;lt;1%, IHC-PR&amp;lt;1% and IHC-HER2 0-1+ and FISH negative if HER2 IHC 2/3+. All patients had standard of care neoadjuvant chemotherapy (NAC) in our hospital. Patients with at least 2 years of documented follow up and only TNBC of no special type on core needle biopsy (CNB) were included. We evaluated the predictive value of patient factors (age, BMI, symptomatic/screening-detected), imaging (micro-MG) and tumor related factors as reported in the pathology-report (grade, cT, focality, cN, lymphovascular invasion, accom-DCIS) for pCR (defined as pT0-TisN0). We used distant relapse rate and death to evaluate outcome. The Cox proportional hazards model was used to analyze the effect of pCR and accom-DCIS on distant relapse rate as well as overall survival (OS) in a multivariate model (corrected for size, nodal state, grading). Results are presented as hazard ratios (HR) with 95% confidence intervals (CI). Results The study contains 219 patients; accom-DCIS was reported in 53/219 (24.2%) CNB’s; pCR was achieved in 90/219 (41,1%). Patient related factors were comparable in patients who achieved pCR and those who had residual disease. Unifocal, smaller clinical size tumors and high tumor grade were significant predictors for pCR in our series. Analysis of 194 available mammographies showed micro-MG in 63/194 (32.5%). Micro-MG predicted for residual disease after NAC [HR = 3.350; 95% CI (1.708 - 6.569), p=0.005]. Accom-DCIS was a strong negative predictor of pCR [HR = 3.333; 95% CI (1.558 - 7.143), p=0.002)] and was associated with more distant relapse and worse survival [HR = 2.664; 95% CI (1.575 - 4.505), p=0.003]. pCR was strongly associated with a lower distant relapse rate and a better OS [HR = 2.210; 95% CI (1.282 - n3.811), p=0.004]. In the 129 cases without pCR, remaining tumor size [HR = 1.019; 95% CI (1.012 - 1.025), p=&amp;lt; 0,001), ypN [HR = 1.917; 95% CI (1.539 - 2.388), p=&amp;lt; 0,001) and presence of LVI [HR = 3.720; 95% CI (2.057 - 6.728), p=&amp;lt; 0,001] significantly predicted for secondary metastasis. There was only a trend towards more distant relapses if accom-DCIS was found in the resection specimen in those who had residual disease [HR = 1.347; 95% CI (0.780 - 2.325), p=0.2855]. Conclusion Presence of accom-DCIS in CNB as well as micro-MG predicts for less pCR in TNBC. Accom-DCIS in CNB is associated with more distant relapse and worse OS. For accom-DCIS on resection specimen, there was only a tendency towards more distant relapses. Citation Format: Jan Ardui, Sophie Vandamme, Chantal Van Ongeval, Giuseppe Floris, Hava Izci, Hans Wildiers, Kevin Punie, Tatjana Geukens, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Annouschka Laenen, Caroline Weltens, Hilde Janssens, Patrick Neven. The presence of ductal carcinoma in situ in core needle biopsy and microcalcifications on mammography in TNBC is associated with a lower pCR and worse long term outcome [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-07.

Surgical Management of Breast Cancer in Turkey: a 30-Year Single-Center Retrospective Study of 2531 Patients

Mastectomy and lumpectomy are well-established surgical methods for the surgical treatment of breast cancer. The comparison of these methods within the 30-year period in terms of clinicopathological characteristics, recurrence, and survival patterns is required in order to provide aid in clinical decision-making. A total of 2531 women who underwent mastectomy or lumpectomy between 1982 and 2012 for primary invasive breast tumors were compared. Starting from 2003, similar variables for patients with primary invasive breast tumors who underwent sentinel node biopsy (SNB) were presented. Mastectomy was performed in 1870 patients and lumpectomy in 661. The median follow-up was 38 months for all patients. The ratio of mastectomy was lower for the patients who underwent SNB. There was no significant difference in breast cancer-related survival or disease-free survival between lumpectomy and mastectomy even after adjusting for the clinicopathological variables. Lumpectomy and mastectomy demonstrate similar survival rates for patients with invasive breast carcinoma. Tumor grade, stage, hormone receptor status, lymphovascular invasion, and distant recurrence have an impact on breast cancer-related survival.

The impact of aspirin use on breast cancer subtype and clinical course

BackgroundThe use of aspirin has been associated with improved survival in patients with breast cancer, but the results have been mixed. We aim to analyze the impact of aspirin use before or after breast cancer diagnosis on breast cancer clinical characteristics and outcomes. Materials and MethodsWe performed a single-institution, retrospective analysis of 1113 women diagnosed with operable breast cancer between 1995 and 2015. Patients were grouped according to their aspirin use: never (944), before diagnosis (79), and after diagnosis (90). Clinical variables, overall survival (OS), and disease-free survival (DFS) were compared between groups. ResultsWomen using aspirin before diagnosis were older, more likely to be black, and to have associated medical comorbidities than patients in other groups (all P <0.001). These patients were also more likely to present with hormone receptor–negative cancers, including triple-negative breast cancer (P = 0.002). Aspirin use before diagnosis was associated with a worse OS in univariate and multivariate analyses (both P <0.001), but there were no other differences in OS or DFS related to aspirin use. ConclusionsDespite a potential impact on tumor subtype in patients using aspirin before their breast cancer diagnosis, aspirin use does not appear to alter breast cancer–related survival.

Abstract P1-07-15: The outcomes for super elderly patients over 80 years old after breast cancer surgery

Abstract (Purpose) Considering the dramatic increase in average life expectancy throughout the world, the management of super-elderly patients over 80 years old (SEP) with breast cancer has become a global issue. However, there have been few clinical trials for SEP until now. The reasons for this were a small population, unpredictable prognosis, a large number of non-cancer-related deaths and a lower function of multiple organs in SEP. Surgical treatment or post-operative treatment based on evidence of clinical trials for SEP has also not been unclear. We hypothesized that the outcome of SEP with breast cancer compared with other ages were similarly depended on the breast cancer subtypes. The aim of this study was to clarify the breast cancer related survival (BRS) rate and overall survival (OS) rate at 5years for SEP according to breast cancer subtype. (Methods) We retrospectively analyzed 407 patients over 80 years old at initial operation between April, 1994 and April 2015 from 4 institutions of Chiba Youth Breast Oncology Research Group. Overall, 366 patients with stage I to Stage IIIc were included. 41 patients with Stage 0 or IV were excluded in this study. We compared the clinical characteristics, OS and BRS rates among the breast cancer subtype: such as ER positive HER2 negative (ER group), ER negative HER2 negative (TN group), ER negative HER2 positive (HER2 group) and ER positive HER2 positive (ER/HER2 group). Univariate and multivariate analyses were performed to identify the factors of Tumor size, Lymph node, Ly, ER, HER2 and characteristics, associated with the OS and BRS. (Results) The median age of the 366 patients was 83 years (range 80-96 years).The median follow-up duration was 32 months (range, 2-120). During the follow-up period, 25 (9.4%) patients in the ER group, 19 (27.5%) in TN group, 4 (22.2%) in HER2 group and 2 (20.0%) patients in ER-HER2 group died. The 5 year OS and BRS rates were 89.2%, 97.1% in ER group, 64.6%, 81.2% in TN group, 61.5%,33.3% in HER2 group and 83.3%, 100% in ER-HER2 group, respectively. Univariate and multivariate analyses revealed that ER was one prognostic factor to OS and BRS. ER positive patients treatment with Aromatase inhibitor had significantly longer survival rates than treatment with Tamoxifen or no treatment (p=0.05). There were no significant differences in OS or BRS of TN patients according to the use of chemotherapy (n=7) versus non treatment (n=61). (Conclusions) The prognosis and clinical course of super elderly patients with breast cancer depended on subtype. Adjuvant therapy for ER group was one prognostic factor to OS and BRS. Citation Format: Nakamura R, Matsuzaki H, Sakamoto M, Suda K, Hayama S, Sangai T. The outcomes for super elderly patients over 80 years old after breast cancer surgery. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-15.

In-Depth Evaluation of the AJCC 2010 Staging System for Luminal-like Breast Cancer-An Analysis from a Free-Standing Cancer Hospital

Purpose: Hormonal receptor (HR) positive breast cancer biologically differs from human epidermal growth factor receptor-2 (HER2) positive disease. The purpose of this study was to re-visit the current AJCC staging system in luminal-like (HR positive and HER2 negative) breast cancer.Materials and Methods: A total of 2051 breast cancer patients treated between 1990 and 2008 were included in this study who met the following criteria: 1) surgery as first treatment; 2) pathology stage I-III; 3) HR positive; and 4) HER2 negative. The T- and N-stage were each re-visited to examine their correlation with 5-year breast cancer-related survival (BCRS).Results: According to the AJCC 2010 staging system, the stage I patients showed a 5-year BCRS of 98.9%; stage IIA: 95.8%; stage IIB: 94.0%; stage IIIA: 90.4%, and stage IIIC: 75.8% (p＜0.001). Re-visiting the T-classification, the 5-year BCRS in T ≤ 0.5 cm N0 patients was same as that of T 1.1-1.5 cm N0 patients (98.4% versus 99.2%); the 5-year BCRS in T1.6-2 cm N1 and N2 patients were no better than those of T ＞2 cm N1 and N2 patients (91.2% and 86.5% versus 94.1% and 88.8%). For the nodal stage, the 5-year BCRS were 91-98.0% for node-negative to 5-node positive patients; the 5-year BCRS were around 80-90% for nodal positivity of 6 to 12, and then dropped below 80% for patients with more than 12 involved nodes.Conclusions: The AJCC 2010 staging system overestimated the risk of breast cancer-related death in early stage luminal-like breast cancer in our hospital. Tumor size 1.5 cm is a crucial point to determine extensive nodal involvement and long-term survivals. Patients with 1-5 positive lymph nodes still had a 5-year BCRS rate exceeding 90%. Given our results, a modification for the current staging system is warranted if other hospitals, especially in Taiwan and Asia, have observed similar outcomes.

Bayesian Method for Modeling Male Breast Cancer Survival Data

With recent progress in health science administration, a huge amount of data has been collected from thousands of subjects. Statistical and computational techniques are very necessary to understand such data and to make valid scientific conclusions. The purpose of this paper was to develop a statistical probability model and to predict future survival times for male breast cancer patients who were diagnosed in the USA during 1973-2009. A random sample of 500 male patients was selected from the Surveillance Epidemiology and End Results (SEER) database. The survival times for the male patients were used to derive the statistical probability model. To measure the goodness of fit tests, the model building criterions: Akaike Information Criteria (AIC), Bayesian Information Criteria (BIC), and Deviance Information Criteria (DIC) were employed. A novel Bayesian method was used to derive the posterior density function for the parameters and the predictive inference for future survival times from the exponentiated Weibull model, assuming that the observed breast cancer survival data follow such type of model. The Markov chain Monte Carlo method was used to determine the inference for the parameters. The summary results of certain demographic and socio-economic variables are reported. It was found that the exponentiated Weibull model fits the male survival data. Statistical inferences of the posterior parameters are presented. Mean predictive survival times, 95% predictive intervals, predictive skewness and kurtosis were obtained. The findings will hopefully be useful in treatment planning, healthcare resource allocation, and may motivate future research on breast cancer related survival issues.

Progesterone receptor loss identifies Luminal B breast cancer subgroups at higher risk of relapse

The immunohistochemical (IHC) evaluation of estrogen receptor (ER), progesterone receptor (PgR), Ki-67 and HER2 is considered a surrogate means for identifying the molecular subtypes of breast cancer with different prognosis. We explored patterns of recurrence in 4837 women with breast cancer defined as Luminal B (ER-positive and/or PgR-positive, HER2 positive and/or Ki-67≥14%) by IHC classification. We evaluated four subgroups within the Luminal B subtype according to HER2 expression and PgR status. Patients within the ER+/PgR+/HER2- subgroup presented a 5-year breast cancer-related survival (BCS) of 97% (95% confidence interval (CI), 96-97) and overall survival (OS) of 95% [95% CI, 95-96], the best survivals of the Luminal B subgroups. In the multivariate analysis, the ER+/PgR-/HER2- subgroup was associated with a reduced BCS (HR 1.71; 95%CI, 1.25-2.35) and OS (HR 1.47; 95%CI, 1.10-1.96) when compared with the ER+/PgR+/HER2- subgroup. Also patients within the ER+/PgR-/HER2+ subgroup had a reduced BCS (HR 1.93; 95%CI, 1.32-2.83) and OS (HR 1.62; 95%CI, 1.14-2.30) when compared with ER+/PgR+/HER2- subgroup. On the other hand, no statistically significant differences were found with regard to BCS and OS among patients with ER+/PgR+/HER2+ and patients with ER+/PgR+/HER2- disease. PgR loss identifies Luminal B breast cancer subgroups at higher risk of relapse and death, both with HER-2-positive and HER-2-negative disease.

Prognosis in women with small (T1mic,T1a,T1b) node-negative operable breast cancer by immunohistochemically selected subtypes

Knowledge is limited about prognostic significance of breast cancer subtypes among women with small invasive node-negative breast tumours. We explored patterns of recurrence in 1691 women with pT1mic/T1a/T1b, pN0 and M0 breast cancer according to four immunohistochemically defined tumour subtypes: (i) Luminal A (ER-positive, PgR-positive, HER2-negative and Ki-67 < 14%); (ii) Luminal B (ER-positive and/or PgR-positive, HER2-positive and/or Ki-67 ≥ 14%); (iii) HER2-positive, both endocrine receptors absent; and (iv) Triple Negative. At multivariate analysis, women with the Triple Negative breast cancer subtype had an increased risk of loco-regional relapse (LRR) (Hazards Ratio (HR) 3.58; 95%CI: 1.40-9.13) and breast cancer related events (HR 2.18; 95%CI: 1.04-4.57). Overall, Luminal B subtype was not associated with a statistically significant increased risk of recurrence compared with Luminal A, while patients with Luminal B subtype tumours overexpressing HER2 had a 2 fold risk of reduced breast cancer related survival (BCS), but not an increased risk of LRR and distant metastases. Women with HER2 breast cancer subtype had a statistically significant increased risk of LRR (HR 4.53; 95%CI: 1.56-13.1), distant metastases and reduced BCS (HR 3.22; 95%CI: 1.44-7.18) and overall survival (HR 2.87; 95%CI: 1.05-7.89) when compared with the Luminal A subtype, at multivariate analysis. In conclusion, women with small size, node-negative, breast cancer are at higher risk of relapse if with HER2-positive endocrine receptor absent or Triple Negative disease.

Clinical Significance of Annexin A1 Expression in Breast Cancer

PurposeThe expression of Annexin A1 (ANXA1) is known to be reduced in human breast cancer; however, the role of ANXA1 expression in the development of breast cancer remains unclear. In this study, we determined the relationship between the expression features of ANXA1 and the prognostic factors of breast cancer.MethodsHuman breast tissues were obtained from patients specimens who had undergone breast surgery or core needle biopsies. The patterns of ANXA1 expression were analyzed by immunohistochemical staining in relation to histopathological diagnosis, clinical characteristics and outcomes.ResultsOne hundred eighty-two cases were included and the mean age of the patients was 46.34 ± 11.5 years. A significant loss of ANXA1 expression was noted in both ductal carcinoma in situ (DCIS) and invasive carcinomas compared to normal breast tissues (p<0.001) and benign breast diseases (p<0.001). There was a significant alteration in ANXA1 expression according to hormone receptor status (p<0.001), cancer intrinsic type (p<0.001), and nuclear grade (p=0.004) in invasive cancer. In a univariate analysis, ANXA1 positivity tended to be related with poor breast cancer-related survival (p=0.062); however, the same results was not realized in multivariate results (p=0.406). HER2 overexpression and TNM staging were significantly associated with relapse-free survivals (RFS) in the multivariate analysis (p=0.037, p=0.048, respectively). In particular, in node-positive patients (p=0.048), HER2 overexpressed patients (p=0.013), and non-triple negative breast cancer patients (p=0.002), ANXA1 overexpression was correlated with poor RFS.ConclusionAlthough significant loss of ANXA1 expression was noted in breast cancer including DCIS and invasive carcinoma, in cases of invasive cancer, overexpression of ANXA1 was related to unfavorable prognostic factors. And these results imply that ANXA1 plays dualistic roles and is involved in variable mechanisms related to cancer development and progression.

A Systematic Review of the Clinical Evidence to Guide Treatment Recommendations in Breast Reconstruction Based on Patient- Reported Outcome Measures and Health-Related Quality of Life

Advances in breast cancer diagnosis and management have produced significant improvements in disease-free and breast cancer related survival. Consequently, there is increasing focus on the quality of long-term cancer survivorship. Of the 44,000 women diagnosed annually in the United Kingdom, 30% to 40% are required to undergo mastectomy. During the past 30 years, significant technical advances in breast reconstruction have increased performance of this surgical practice as a means to potentially improve health-related quality of life (HRQoL) for breast cancer survivors. Breast reconstruction studies increasingly aim to assess more discriminating outcomes based on the patients' own perception of the surgical result and its effect on HRQoL. This incremental output in HRQoL evaluation is being fuelled by both healthcare providers and official bodies such as the Food and Drug Administration, together with demands for more comprehensive comparative effectiveness data to permit fully informed consent by patients. In this systematic review, the authors apply inclusion and exclusion criteria to effectively screen 1012 abstracts identified in the field of HRQoL in breast reconstruction between 1978 and 2009. Each study was evaluated with respect to its design and statistical methodology. Each was reviewed with a recommended standard checklist of methodological requirements as described by Efficace et al (J Clin Oncol. 2003;21:3502-3511). A total of 34 papers that included HRQL outcomes in breast reconstruction were identified and reviewed in detail. The majority of studies were retrospective in nature with significant inherent limitations. Specifically, they were compromised by potentially biased patient recall. Most of these studies lacked both an a priori outcome of interest and statistical rigor jeopardizing estimations of potential effect size. In addition, more than 90% of the studies failed to report or describe missing data. Thirteen studies provided level I (n = 2) and II (n = 11) evidence. While these studies benefited from more robust design, the majority used generic instruments such as 36-item short form (SF-36), which may not be sufficiently sensitive to measure changes consequent to breast reconstruction (ie, effect on body image or psychosocial well-being). Furthermore, these studies were generally underpowered to detect meaningful clinical difference or to permit subgroup analyses. Further limitations included reliance on single center design that may negatively impact generalizability and deficiencies in reporting the number and types of surgical complications, which potentially has an effect on HRQoL outcomes. This systematic review reveals tendency for sound scientific methodology in HRQoL to be undermined by poorly designed and underpowered studies. In the current healthcare environment, patients and providers increasingly seek meaningful data to guide clinical decisions; policy makers are similarly in need of a rigorous patient-centered, comparative effectiveness data to inform national level decision-making. In light of this and the limitations of the existing published data, there is a pressing need for further Level I and II evidence in the form of randomized controlled trials as well as well-designed, multicenter prospective longitudinal studies in breast reconstruction. Such studies should incorporate sensitive and condition-specific patient-report outcome measures, provide adequate sample sizes, and respect established guidelines for rigorous HRQoL methodology.

Phosphorylated c-Src predicts clinical outcome in triple negative breast cancers.

Abstract Abstract #2076 Background: Recent in vitro evidence suggests that c-Src inhibitors may be effective in inhibiting growth of basal-type/"triple-negative" cell lines. However there is little evidence to support this in clinical specimens. Development of treatment for women with these aggressive ER, PR and HER2 negative cancers is particularly important with the lack of current effective therapies. Activation of Src family members are associated with phosphorylation at two sites Y419: the classical activation site and Y215, known to induce a 50-fold increase in activation.&amp;#x2028; The aim of the current study is to assess if expression levels and/or activation of Src kinase is associated with clinical outcome measures in ER and HER2 negative human breast cancers.&amp;#x2028; Methods: Tissue microarrays consisting of 172 ER and HER2 negative breast cancer tumors were constructed. Median clinical follow up was 5.9 years with 64 deaths attributed to breast cancer. Immunohistochemistry was performed using antibodies to c-Src, pSrc419 and pSrc215 (antibodies to Y419 and Y215 will detect phosphorylation of c-Src and other family members). Expression was assessed by two independent scorers. All statistical calculations were performed using SPSS 15, including Kaplan-Meier life table analysis with log rank testing of differences in breast cancer related survival.&amp;#x2028; Results: Membrane expression of c-Src, pSrc419 and pSrc215 was rarely observed and was not associated with outcome. However cytoplasmic expression was frequently observed. There was a trend towards reduced survival seen with c-Src and pSrc419 overexpression. In direct contrast pSrc215 was significantly associated with increased disease specific survival and was independent on multivariate analysis.&amp;#x2028; We then hypothesised that activation of c-Src via Y419 but not Y215 was driving the observed association with outcome. Indeed c-Src positive, pSrc419 positive and pSrc215 negative patients have a 25% 5yr survival rate, in comparison all other patients in the cohort had a 72% 5yr survival rate.&amp;#x2028; &amp;#x2028; Discussion: These results support the in vitro studies suggesting Src family members are associated with progression of triple negative breast cancers. If confirmed in a larger cohort, these results suggest that Src family members may offer a therapeutic target for triple negative cancers. However care must be taken to appropriately select patients with phosphorylation only at Y419 and not Y215. The reason why Y215 phosphorylation is associated with improved outcome requires further investigation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2076.

Have we been guilty of ageism in the primary treatment of breast cancer?

The current issue of the British Journal of Cancer contains a well-conducted meta-analysis of six small randomised trials comparing appropriate surgery, with or without tamoxifen to tamoxifen alone as primary treatment for elderly women with operable breast cancer. The meta-analysis included 517 women treated in studies of surgery plus tamoxifen compared to tamoxifen alone, and 247 women treated in studies of surgery compared to tamoxifen alone. A meta-analysis of each subgroup showed significant improvement in progression-free survival (hazard ratio (HR)=0.55; 95% confidence interval (CI) 0.39–0.77; P=0.006) for surgery in comparison to adjuvant tamoxifen and 0.65 (95% CI 0.53–0.81; P=0.0001) for surgery plus tamoxifen in comparison to tamoxifen alone. Overall survival was not improved in the meta-analysis of surgery alone compared to tamoxifen alone, but was marginally significantly better for adjuvant tamoxifen plus surgery compared to adjuvant tamoxifen alone (HR=0.86; 95% CI, 0.83–1; P=0.06). Interestingly, a previous meta-analysis by Mustacchi et al (1994) also suggested a marginally improved risk ratio of 0.86 (P=0.09) for adjuvant tamoxifen and surgery in comparison to tamoxifen alone for overall survival and 0.70 (P<0.05) for breast cancer-related survival.

Selective Application of Axillary Node Dissection in Elderly Women with Early Breast Cancer

Routine use of axillary lymph node dissection (ALND) has been questioned in elderly women. This study examines whether selective application of ALND in early stage breast cancer affects breast cancer-related survival. From the Surveillance, Epidemiology, and End Results (SEER) database, records of women >or=70 years of age with stage I or II breast cancer diagnosed between 1990 and 1995 were reviewed. Hazard ratios (HR) of cause-specific survival (CSS) between women receiving ALND and those who did not were compared. To minimize the potential for bias in the selection of women to receive ALND, HR of CSS was compared within propensity analysis deciles. 20,151 women entered the analysis. Median follow up was 6 years (interquartile range 4.33-7.67 years). Seventy-five percent underwent ALND. Women with higher risk disease and younger age were more likely to undergo ALND. Five year unadjusted CSS in women who did and did not receive ALND was 92.1% and 90.6%, respectively, with a HR of 0.85, P = 0.002. Using the propensity analysis method, the adjusted HR for CSS associated with ALND was 0.89, P = 0.066. After adjusting for differences in the probability of receiving ALND, no clinically or statistically significant difference in survival was observed among women who received ALND when compared with those who did not, although we could not account for differences in co-morbidity or use of systemic therapy between groups. Surgeons select elderly women with early stage breast cancer for ALND with a negligible impact on CSS.

Expression of Matrix Metalloproteinase (MMP)-2 and MMP-9 in Breast Cancer with a Special Reference to Activator Protein-2, HER2, and Prognosis

In the present study, we investigated the expression and prognostic value of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer as well as their relation to transcription factor activator protein (AP)-2 and HER2 oncogene. The role of invasion and metastasis-promoting MMPs and their potential regulators, AP-2 and HER2, is currently still unclear in breast cancer. MMP-2 and MMP-9 expressions were analyzed immunohistochemically in a large prospective series of 421 breast cancer patients diagnosed and treated between 1990 and 1995 at Kuopio University Hospital (Kuopio, Finland). The relation of MMP-2 and MMP-9 expressions to AP-2, HER2, clinicopathological data, and survival was investigated. Both MMP-2 and MMP-9 were expressed in the cytoplasm of malignant and stromal cells. High expression of MMPs in carcinoma cells was related to small tumors (T1, stage I), whereas positive stromal expression of MMPs was associated with aggressive factors. High expression of MMP-2 and MMP-9 in carcinoma cells, but not in stromal cells, was related to high AP-2 expression. Positive stromal MMP-2 expression was associated with HER2 overexpression in the whole patient group and in the node-negative patient subgroup. Positive stromal MMP-9 expression was related to HER2 overexpression in estrogen receptor (ER)-positive disease. In the univariate survival analysis, positive stromal MMP-9 predicted shorter recurrence-free survival (RFS; P=0.0389) and breast cancer-related survival (BCRS; P=0.0081) in ER+ disease, especially in the subgroup of ER+ tumors of < or =2 cm in diameter (T1; P=0.0031 for RFS, and P=0.0089 for BCRS). High MMP-9 expression in cancer cells predicted longer RFS (P=0.0351) in the whole patient group. In the multivariate analysis of the whole patient group, the independent predictors of shorter RFS were reduced MMP-9 expression in carcinoma cells (P=0.0248), HER2 overexpression (P=0.0001), and advanced-stage disease (P=0.0002). Shorter BCRS was predicted by advanced-stage disease (P <0.0001). Expression of MMP-2 and MMP-9 in breast cancer seems to be partly related to expression of AP-2 and HER2. Positive stromal MMP-9 expression predicts poor survival in the hormone-responsive small tumors, whereas MMP-9 expression in carcinoma cells favors survival. Evaluation of MMP-9 expression seems to add valuable information on breast cancer prognosis.

Expression of HER2 and its association with AP-2 in breast cancer

The aim of the study was to investigate the relationship between the expression of human epidermal growth factor receptor 2 (HER2) and activator protein 2 (AP-2), as well as the prognostic significance of HER2 in breast cancer. HER2 and AP-2 expressions were immunohistochemically (IHC) analysed in a large prospective, consecutive series of 425 breast cancer patients diagnosed and treated between 1990 and 1995 at the Kuopio University Hospital, Kuopio, Finland. In a subset of patients ( n=71), the gene amplification status was examined by using a chromogenic in situ hybridisation (CISH) analysis. Expression of HER2 was studied in relation to AP-2, clinicopathological parameters and patients' survival. Pathological membranous overexpression of the HER2 receptor was seen in 13% of the carcinomas, which was related both to gene amplification (78% of the cases) and high nuclear expression of AP-2 (67%, P=0.007). HER2-positivity was most often seen in carcinomas having both high nuclear and high cytoplasmic AP-2 expression ( P<0.001). In the univariate survival analyses HER2-positivity predicted a shorter recurrence-free survival (RFS) ( P<0.0001) and a shorter breast cancer-related survival (BCRS) ( P=0.0063) in the whole patient group, as well as in the subgroup of node-negative patients. In the node-positive patients, HER2-positivity predicted only a shorter RFS. Combined expression of HER2 and nuclear AP-2 resulted in the separation of four groups with different prognoses, the best prognosis being for patients in the HER2-/AP-2+ group and the worse prognosis for those in the HER2+/AP-2- group. In the multivariate survival analyses, HER2-positivity independently predicted a shorter RFS in the whole patient group ( P=0.0067), as well as in the subgroup of node-positive patients ( P=0.0209). In conclusion, pathological membranous overexpression of the HER2 receptor in breast cancer is related both to gene amplification and a high AP-2 expression. Combining HER2 and AP-2 expressions may provide valuable information on the prognosis of breast cancer patients.

P21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis

Aims: To evaluate the expression and prognostic relevance of p21WAF1 in breast cancer and to investigate its association with p53, activator protein 2 (AP-2), and cell proliferation (as assessed by...