Early Operable Primary Breast Cancer Research Articles

Liver Kinase B1-A Potential Therapeutic Target in Hormone-Sensitive Breast Cancer in Older Women.

Background: The role of liver kinase B1 (LKB1), a serine/threonine kinase, has been described in the development of PeutzJagher’s syndrome, where a proportion (~45%) of patients have developed breast cancer in their lifetime. Cell line studies have linked LKB1 with oestrogen receptors (ER) and with the Adenosine monophosphate-activated protein kinase (AMPK) pathway for energy metabolism. However, limited studies have investigated protein expression of LKB1 in tumour tissues and its intracellular relationships. This study aimed to investigate the intracellular molecular relationships of LKB1 in older women with early operable primary breast cancer and its correlation with long-term clinical outcome. Methods: Between 1973 and 2010, a consecutive series of 1758 older (≥70 years) women with T0-2N0-1M0 breast carcinoma were managed in a dedicated facility. Of these, 813 patients underwent primary surgery, and 575 had good quality tumour samples available for tissue microarray construction. LKB1 was assessed in 407 cases by indirect immunohistochemistry (IHC). Tumours with 30% or more of cells with cytoplasmic LKB1 expression were considered positive. LKB1 expression was compared with tumour size, histological grade, axillary lymph node stage, ER, PgR, EGFR, HER2, HER3, HER4, BRCA1&2, p53, Ki67, Bcl2, Muc1, E-Cadherin, CD44, basal (CK5, CK5/6, CK14 and CK17) and luminal (CK7/8, CK18 and CK19) cytokeratins, MDM2 and MDM4, and correlated with long-term clinical outcome. Results: Positive LKB1 expression was seen in 318 (78.1%) patients, and was significantly associated with high tumour grade, high Ki67, over-expression of HER2, VEGF, HER4, BRCA2, MDM2 and negative expression of CD44 (p < 0.05). There was no significant correlation with tumour size, axillary lymph node status, ER, PgR, p53, basal or luminal cytokeratins, Bcl2, Muc1, EGFR, HER3, MDM4, E-cadherin and BRCA1. LKB1 did not show any significant influence on survival in the overall population; however, in those patients receiving adjuvant endocrine therapy for ER positive tumours, those with positive LKB1 had significantly better 5-year breast cancer specific survival when compared to those without such expression (93% versus 74%, p = 0.03). Conclusion: LKB1 expression has shown association with poor prognostic factors in older women with breast cancer. However, LKB1 expression appears to be associated with better survival outcome among those patients receiving adjuvant endocrine therapy. Further research is required to explore its potential role as a therapeutic target.

Correction: Oestrogen receptor negative early operable primary breast cancer in older women-Biological characteristics and long-term clinical outcome.

[This corrects the article DOI: 10.1371/journal.pone.0188528.].

Oestrogen receptor negative early operable primary breast cancer in older women-Biological characteristics and long-term clinical outcome.

BackgroundOlder women are at the greatest risk of breast cancer development and a considerable number present with comorbidities. Although the majority of breast cancers in this age group express oestrogen receptor (ER), which makes endocrine therapy (primary or adjuvant) feasible, given the huge size of the elderly population, there remains a significant number of patients, in absolute term, whose tumours do not express ER and their management is challenging.MethodsOf a consecutive series of 1,758 older (≥70 years) women with early operable primary breast cancer managed in a dedicated service from 1973–2010, 252(14.3%) had ER-negative (histochemical (H) score ≤50) tumours. Their clinical outcome was retrospectively reviewed and tumour samples collected from diagnostic core biopsies were analysed for progesterone receptor (PgR), HER2 and Ki67 using immunohistochemistry.ResultsThe commonest primary treatment was surgery (N = 194, 77%) followed by primary endocrine therapy (14.3%), primary radiotherapy (5.6%) and supportive treatment only (3.1%). Among the patients undergoing surgery, most of them had grade 3 (78.1%) and node-negative disease (62.2%). Some of them (21.1%) received postoperative radiotherapy. At a median follow-up of 37.5 months, 117 patients had died, out of which 48.6% were due to breast cancer. For those who underwent surgery, the regional and local recurrence rates were 2% and 1.1% per annum respectively. For those who received primary endocrine therapy, 38% progressed at 6 months, however all patients who had primary radiotherapy achieved clinical benefit at 6 months. Regardless of treatment given, the 5-year breast cancer specific and overall survival rates were 70% and 50% respectively. Biological analysis based on good quality needle core biopsy specimensfrom181 patients showed that 26.8% (N = 49), 16.9% (N = 31) and 70.7% (N = 70)expressed positivity for PgR, HER2 and Ki67 respectively. No correlation between these biomarkers and breast cancer specific survival was demonstrated.ConclusionOestrogen receptor negative early operable primary breast cancer in older women is associated with poor prognostic features in terms of biology and clinical outcome. Surgery appears to produce the best outcome as a primary treatment, however for those where neither surgery nor chemotherapy is appropriate, primary radiotherapy can be beneficial.

Relationships of cyclin E with clinical outcome and biomarkers in older women with early operable primary breast cancer.

e12031 Background: Cyclin E is one of the factors responsible for transition from G1 to S phase of cell division. Cytoplasmic cyclin E has recently been shown to be associated with the greatest risk of breast cancer recurrence (Hunt KK et al. Clin Cancer Res. 2016 Nov 23). This study aimed to analyse intracellular relationships of cyclin E with clinical outcomes and with other biomarkers in a specific patient population. Methods: Over 37 years (1973-2010), 1,758 older (≥70 years) women with early operable (&lt;5cm) primary breast cancer were managed in a dedicated clinic in Nottingham. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray construction and immunohistochemical studies of biomarkers. Cytoplasmic expression of cyclin E with or without nuclear expression was considered positive. Results: Cytoplasmic cyclin E expression was associated with poor clinical outcomes on multivariate analysis (see table below). Cytoplasmic cyclin E expression was significantly associated with negative ER(&lt;0.001), PR(p=0.008), CK19(p=0.009) and positive expression of Ki67(p=0.04), p53(p=0.02), CK5(p=0.001), CK17(p=0.04), LKB1(p=0.04), HER3(p=0.03) and HER4(p=0.04). No correlation was found with HER2, BRCA2, CK5/6, CK18, EGFR, CD44, MDM2, MDM4, E-Cadherin and MUC1. Conclusions: Cytoplasmic cyclin E is associated with poor clinical outcome and biomarkers of poor prognostic significance in older population with breast cancer. Cyclin E may serve as a potential therapeutic target in future. [Table: see text]

Differing pattern of biological characteristics of early operable primary breast cancer according to age.

e23272Background: Emerging evidence suggests that breast cancer in the older population tends to have less aggressive biological characteristics. This study aimed to explore a possible differing pa...

The potential value of comprehensive geriatric assessment in evaluating older women with primary operable breast cancer undergoing surgery or non-operative treatment--a pilot study.

Breast cancer in older women raises a number of discrete issues, including how healthcare professionals can best decide which patients are candidates for surgery. A pilot study involving women aged ≥70years newly diagnosed with early operable primary breast cancer was conducted aiming to explore the potential value of comprehensive geriatric assessment (CGA). Decision of primary treatment followed consultation with the clinical team and was not guided by any aspect of this study. CGA, using a validated cancer-specific tool, was conducted within 6weeks and 6months after diagnosis, complemented by formal measures of quality of life (QOL) (using EORTC QLQ-C30 and QLQ-BR23) and semi-structured interviews. A total of 47 female patients with a new diagnosis of clinically early (stage 1 or 2; cT0-2N0-1M0) operable primary breast cancer proven histologically, were recruited. CGA determined that increasing age (≥80years) (p=0.001), greater (≥4) comorbidity (p=0.022), greater number (≥4) of daily medications (p=0.002), and slower (≥19s) timed up and go (TUG) (p=0.016) score were significantly related to non-surgical treatment at 6weeks after diagnosis. Baseline QOL scores were generally good and they remained stable at 6months follow-up. As opposed to CGA, there was no correlation between QOL scores and the treatment modality identified. Semi-structured interviews identified themes consistent with findings from QOL assessment. The pilot study confirmed the feasibility of conducting CGA in a research setting which appeared to have value in assessing this patient population. More data will be required to definitively identify the components for geriatric assessment in this setting. The study has now extended into two more centres.

Tamoxifen versus anastrozole as primary endocrine therapy in older women with early operable primary breast cancer.

e11533 Background: Aromatase inhibitors (AIs) have shown superiority over tamoxifen in metastatic, neoadjuvant (for locally advanced disease) andadjuvant settings in postmenopausal women with oestr...

Human epidermal growth receptor-2 overexpressing early operable primary breast cancers in older (≥70 years) women: biology and clinical outcome in comparison with younger (

There is dearth of literature reporting the prevalence and biological characteristics as well as the long-term clinical outcome of human epidermal growth factor receptor-2 (HER2) overexpressing tumours in older women. Currently, research involving trastuzumab at large focuses on the younger population. This study aimed to analyse their biological characteristics and to compare them with their younger counterparts from a single centre with a long-term clinical follow-up. Over 37 years (1973-2010), 1758 older (≥70 years) women with early operable (<5 cm) primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these, 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. Comparison was made with data from a well-characterised younger (<70 years) series (N = 1711) treated between 1986 and 1998 (before adjuvant trastuzumab became standard) in our institution. Forty five (7.6%) and 140 (8.2%) patients from the older and younger series, respectively, had HER2-positive tumours. HER2 overexpression was seen in 45 (7.6%) older women and 140 (8.2%) in younger patients (P = 0.56). HER2 overexpressing tumours in older women when compared with that in their younger counterparts were associated with low Ki67 and high bcl2 expression (P < 0.05). Only 26% of the younger patients and none of the older patients received adjuvant chemotherapy, and no patients at the time received trastuzumab. However, there was no significant difference in the outcome of the two age groups (5-year breast cancer-specific survival rate: <70 years = 65% versus >70 years = 70%, P = 0.51). HER2 overexpressing tumours in older women showed relatively a less aggressive phenotype and did not show any inferior long-term clinical outcome despite not having received chemotherapy when compared with the younger patients. The precise role of different adjuvant systemic therapies in this population needs to be delineated.

Human epidermal growth receptor-2 overexpressing early operable primary breast cancers in older (≥70 years) women: Biology and clinical outcome in comparison with younger (&lt;70 years) patients.

e11608 Background: There is dearth of literature reporting the prevalence and biological characteristics as well as the long-term clinical outcome of HER2 positive tumors in older women. This study aimed to analyse their biological characteristics and compare them with their younger counterparts from a single centre with long-term clinical follow-up. Methods: Over 37 years (1973-2010), 1,758 older (≥70 years) women with early operable (&lt;5cm) primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray (TMA) analysis using immunohistochemistry. Comparison was made with data from a well-characterised younger (&lt;70years) series (N=1,711) treated between1986 - 1998 (before adjuvant trastuzumab became standard) in our institution. Thirty-nine (7.6%) and 140 (8.2%) patients from the older and younger series respectively (p=0.56) had HER2-positive tumours. Results: See Table. Conclusions: The HER2 positive tumours in older women showed relatively less aggressive phenotype and did not show any inferior long-term clinical outcome despite not having received chemotherapy as compared to the younger patients. The precise role of different adjuvant systemic therapies in this population needs to be delineated. [Table: see text]

Biology of primary breast cancer in older women treated by surgery: with correlation with long-term clinical outcome and comparison with their younger counterparts

Background:As age advances breast cancer appears to change its biological characteristics, however, very limited data are available to define the precise differences between older and younger patients.Methods:Over 36 years (1973–2009), 1758 older (⩾70 years) women with early operable primary breast cancer were managed in a dedicated clinic. In all, 813 underwent primary surgery and 575 good quality tumour samples were available for biological analysis. The pattern of biomarkers was analysed using indirect immunohistochemistry on tissue microarrays. Comparison was made with a previously characterised series of younger (<70 years) patients.Results:There was high expression of oestrogen receptor (ER), PgR, Bcl2, Muc1, BRCA1 and 2, E-cadherin, luminal cytokeratins, HER3, HER4, MDM2 and 4 and low expression of human epidermal growth factor receptor (HER)-2, Ki67, p53, EGFR and CK17. Oestrogen receptor and axillary stage appeared as independent prognostic factors. Unsupervised partitional clustering showed six biological clusters in older patients, five of which were common in the younger patients, whereas the low ER luminal cluster was distinct in the older series. The luminal phenotype showed better breast cancer-specific survival, whereas basal and HER2-overexpressing tumours were associated with poor outcome.Conclusion:Early operable primary breast cancer in older women appears as a distinct biological entity, with existence of a novel cluster. Overall older women showed less aggressive tumour biology and ER appeared as an independent prognostic factor alongside the time-dependent axillary stage. These biological characteristics may explain the differences in clinical outcome and should be considered in making therapeutic decisions.

Biological characteristics of triple negative early operable primary breast cancer in older women in comparison with their younger counterparts

O1 Biological characteristics of triple negative early operable primary breast cancer in older women in comparison with their younger counterparts B.M. Syed, A.R. Green, D.A.L. Morgan, I.O. Ellis, K.L. Cheung*. Division of Breast Surgery, University of Nottingham, Nottingham, UK, Divisions of Pathology, University of Nottingham, Nottingham, UK, Department of Oncology, NottinghamUniversity Hospitals, Nottingham, UK

Novel biological features of early operable primary breast cancer in older women—Based on molecular characterisation using partitional clustering

Novel biological features of early operable primary breast cancer in older women—Based on molecular characterisation using partitional clustering

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.

Abstract 688: Lamin A/C a novel potential prognostic marker in early operable primary breast cancer

Abstract Background Lamins A/C, a major component of the nuclear lamina of highly differentiated mammalian cells is encoded by LMNA gene. Its involvement in tumorignesis is of interest due to its role in maintaining the nuclear integrity, regulation of gene expression, cell proliferation and apoptosis. Reduced lamin A/C expression in cancer has been reported to be a sign of poor prognosis. However there is few data on its clinical significance in breast cancer. This study aimed to evaluate expression of lamin A/C in a large series of patients with early operable invasive breast cancer; we analyzed the association of lamin A/C expression with clinicopathological parameters and long term clinical outcome. Methods Using immunohistochemistal staining of tissue microarrays, expression of Lamin A/C was evaluated in a large well characterized series of early operable invasive breast carcinoma patients (n=938) obtained from Nottingham Tenovus Primary Breast Carcinoma Series between the period of 1988 and 1998 who underwent primary surgery. All patients were managed following a standard management guidelines by a single team of clinicians and the decision of adjuvant systemic therapy was made on the basis of Nottingham prognostic Index (NPI) score and hormonal status. Using X-tile bioinformatics software a positivity cut-off of H-score &amp;gt;150 was found to be most informative. The expression was then correlated with clinicopathological parameters (age, tumour grade, tumour stage, tumour size, nodal status, vascular invasion, and NPI) using Chi-squared analyses. Association of lamin A/C expression with prognosis [loco-regional recurrence, distant metastasis and breast cancer specific survival (BCSS)] was evaluated by Kaplan Meier survival analysis and Cox proportional hazards model was used to assess the statistical independence and significance of the marker on BCSS. Results The median follow-up of patients was 146 months. Positive expression rate of Lamin A/C was 42.2%. (n=398). Lamin A/C expression was significantly associated with low histological grade (p&amp;lt;0.001), tumour size &amp;lt;1.5 cm (p=0.004), good NPI score (p&amp;lt;0.001), absence of vascular invasion (p=0.014) and absence of distant metastasis (p = 0.027). No association was found between cells expressing lamin A/C and lymph node stage, distant metastases, loco-regional recurrence and patient age. Survival analysis showed that lamin A/C positivity was significantly associated with a longer breast cancer specific survival (p = 0.008) but it was not independent of tumour stage, grade or size for predicting BCSS (p=0.304). Conclusion This study suggests lamin A/C expression as a potential prognostic biomarker for early operable invasive breast cancer. Our findings indicate that lamin A/C expressing tumours are associated with better breast cancer specific survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 688. doi:1538-7445.AM2012-688

Molecular characterization of primary breast cancer in older women using partitional clustering and correlation with long-term clinical outcome.

10549 Background: Recent advances in molecular classification of breast cancer have given more insights into management strategies and outcome. However, most of the reported studies are focused on younger patients. We now report its application in a series of older women managed in a single centre with long-term follow-up. Methods: Over 36 years (1973-2009), 2,000+ older (≥70 years) women with early operable primary breast cancer were managed in a dedicated clinic. Of these 831 underwent surgery as primary therapy (and received adjuvant therapies as per unit protocol at the time of diagnosis) and 575 had good quality tumour samples available for tissue microarray (TMA) analysis using indirect immunohistochemistry. H-scores of 19 markers (ER, PR, HER2, Ki67, p53, CK5,5/6,7/8,14,17,18,19, EGFR, bcl2, E-Cadherin, MUC1, CD44, HER3, HER4) were clustered using R (2.11.1, USA). Results: Unsupervised clustering showed 6 clusters. Following identification of their main drivers, 12 markers were selected and the same 6 clusters were reproduced, using K-means and Partitioning Around Medoids (PAM) methods, in 367 patients. Using Predictive Analytics Software (PASW 18, Chicago, Illinois), the following correlation with their clinical outcome was obtained, at a median follow-up of 60 months (longest=106) (Table). Conclusions: When compared with known molecular classification, the cluster with low hormone receptors and high luminal cytokeratins (“low ER luminal”) appears unique to older women, associated with different clinical outcome. Cluster (N/%) Pattern of key markers Breast cancer-specific survival Hormone receptors Luminal markers Basal markers p53 and HER2 5-year (%) 10-year (%) Luminal A (139/37.9) High High Low Low 95 76 Luminal B (92/25.1) ER=High PR=Low High Low Low 90 68 “Low ER luminal” (56/15.3) Low High Low Low 83 63 Basal (30/8.2) Low CK18=Low CK19=High CK7/8=Moderate High p53=High HER2=Low 73 73 Normal like (22/6.0) Low Low Low Low 84 47 HER2 overexpressive (28/7.6) Low High Low High 73 65

Clinical outcome of triple-negative primary breast cancer in older women: Comparison with their younger counterparts.

1057 Background: It is generally believed that triple-negative (ER-/PR-/HER2-) primary breast cancers have poor prognosis. Following surgery, adjuvant chemotherapy is currently the only treatment that could potentially improve survival. On the other hand, the absolute benefit of adjuvant chemotherapy in older women appears small and its precise value remains to be proven. As such its use tends to be very limited in this population. Methods: Over 36 years (1973−2009), 2,000+ older (≥70 years) women with early operable primary breast cancer were managed in a dedicated clinic. Of these 127 patients with triple negative invasive carcinoma (defined as ER/PR = 0% positive cells, HER2 = 1+ or 2+ on IHC and CISH negative) underwent primary surgery and had good quality tumour samples available for tissue microarray (TMA) analysis using indirect immunohistochemistry. The results were compared with their younger (<70 years) counterparts from a previously characterised, consecutive series (N=1,809) treated in the same unit (1986–1998). Among them, there were 342 patients who had triple negative tumors. Results: At a median follow-up of 46 months (longest=204) (≥70 years) and 119 months (longest=135) (<70 years), the results are shown in the table. Conclusions: Despite not having received adjuvant chemotherapy, the older series had clinical outcome similar to the younger patients almost half of which had chemotherapy. This may be due to other biomarkers (in addition to ER/PR/HER2) which have different patterns in these age groups influencing prognosis. The place of adjuvant chemotherapy in the treatment of these patients has yet to be identified. Treatment pattern <70 years ≥70 years With adjuvant chemotherapy 149 (47.0%) 0 Without adjuvant chemotherapy 168 (53.0%) 127 (100%) Outcome at 5 years P value Breast cancer-specific survival 73% 79% 0.39 Local recurrence 10% 14% 0.16 Regional recurrence 11% 14% 0.40 Metastases 30% 27% 0.56

O-42 Early operable primary breast cancer in older (⩾70 years) women (EPCs) – Biology and clinical significance

O-42 Early operable primary breast cancer in older (⩾70 years) women (EPCs) – Biology and clinical significance

Early operable primary breast cancer in elderly (≥70 years) women: Are they biologically different from their younger counterparts?

10547 Background: Biological features of breast cancer seem to change with age. Most studies have small sample size or data collected from multiple centres with different laboratory protocols limiting their importance. This study was part of an ongoing research programme on breast cancer in the elderly, and was conducted in a single breast unit with a dedicated breast histopathology research team. Methods: Over 36 years (1973-2008), 2,000+ elderly (≥70 years) women with early operable primary breast cancer were managed in our dedicated elderly primary breast cancer clinic. Of these 831 underwent surgery as primary therapy and 575 had good quality tumour samples available for tissue microarray (TMA) analysis using indirect immunohistochemistry. A total of 15 biomarkers were measured using pre-defined cut-offs: ≥1% of cells stained considered positive in ER, PR, HER4 and E-Cadherin, ≥5% in p53, ≥10% in CK (5/6, 7/8, 14, 17, 18 and 19), BRCA1, Ki67 and MUC1; HER2 with 3+ score was considered positive. The results were compared with those from a previously characterised, consecutive series (N=1,809) of younger (<70 years) patients with early operable primary breast cancer treated in the same unit between 1986 – 1998. Results: The expression of ER (p<0.001), HER4 (p<0.000), CK14 (p<0.000), CK17 (p<0.02), CK18 (p<0.000) and p53 (p<0.000) increased with advancing age, while the reverse was seen with CK 7/8 (p<0.002), Ki67 (p<0.000), BRCA1 (p<0.000) and E-Cadherin (p<0.000). No change with age was seen in all other biomarkers. Conclusions: The biology of breast cancer appears to change with age, with clear trend seen in a significant number of biomarkers. The pattern is consistent with reduced aggressiveness of the disease with advancing age as shown by increasing expression of ER and cell differentiation markers, and decreasing expression of proliferation markers. This would have potential impact on clinical management and outcome. No significant financial relationships to disclose.

Biomarkers of early operable primary breast cancer in elderly (≥70 years) women (EPC) and their correlation with breast cancer-specific survival (BCSS).

10558 Background: Biological features of breast cancer seem to change with age. Most studies have small sample size or data collected from multiple centres with different laboratory protocols, limi...

Early operable primary breast cancer in elderly (age 70 and older) women (EPC): Changing pattern of management and clinical outcome over 36 years.

624 Background: Over the last few decades, there has been changing availability/application of various factors (e.g., estrogen receptor [ER], axillary status) and evolving evidence from clinical tr...