Patterns of biomarker expression in patients treated with primary endocrine therapy - a unique insight using core needle biopsy tissue microarray.

PURPOSE: Prediction of response to primary endocrine therapy (PET) in older women is based on measurement of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor (HER)-2. This study uses a unique method for construction of core needle biopsy (CNB) tissue microarray (TMA), to correlate expression of a panel of 17 biomarkers with clinical outcome, in patients receiving PET. METHODS: Over 37 years (1973-2010), 1758 older (≥ 70 years) women with operable primary breast cancer were managed in a single institution. Of these, 693 had sufficient good-quality CNB to construct TMA, of which 334 had ER-positive tumours treated by PET with a minimum of 6-month follow-up. A panel of biomarkers was measured by immunohistochemistry (ER, PgR, HER2, Ki-67, p53, CK5/6, CK 7/8, EGFR, BCL-2, MUC1, VEGF, LKB1, BRCA1, HER3, HER4, PTEN and AIB1). Expression of each biomarker was dichotomised into 'low' or 'high' based on breast cancer-specific survival (BCSS). RESULTS: From the panel of biomarkers, multivariate analysis showed: High ER (p = 0.003) and PgR (p = 0.002) were associated with clinical benefit of PET at 6 months, as opposed to progressive disease. High ER (p = 0.0023), PgR (p < 0.001) and BCL-2 (p = 0.043) and low LKB1 (p = 0.022) were associated with longer time to progression. High PgR (p < 0.001) and low MUC1 (p = 0.021) were associated with better BCSS. Expression of other biomarkers did not show any significant correlation. CONCLUSIONS: In addition to ER and PgR; MUC1, BCL-2 and LKB1 are important in determining the outcome of PET in this cohort.

A study of ductal versus non-ductal invasive breast carcinomas in older women: long-term clinical outcome and comparison with their younger counterparts.

Ductal carcinoma is the commonest histological type found in invasive breast carcinomas and may be associated with worse prognosis, when compared to non-ductal carcinoma. Older patients tend to display more favourable tumour biology than younger patients. This study aimed to investigate the significance of histological type and its relationship with clinical outcome in the older group. A total of 808 older (≥70 years) women with early operable primary breast cancer underwent surgery as their primary treatment, followed by optimal adjuvant therapies, in the Nottingham Breast Unit between 1973 and 2009. The histological types of the surgical specimens were reviewed and compared with those in a previously characterised younger (<70 years) series (N = 1,733), in terms of distribution and correlation with clinical outcome. Ductal type was associated with a significantly worse clinical outcome when compared to non-ductal type in the older group in terms of 10-year rates of metastasis-free survival (75 vs 79 %, p = 0.028) and overall survival (44 vs 52 %; p = 0.015). Similar worse clinical outcome was found with the ductal type in the younger group in terms of 10-year rates of metastasis-free survival (65 vs 79 %; p = 0.001) and overall survival (60 vs 78 %; p = 0.001). For all patients with ductal type carcinomas, the older series showed significantly better 10-year metastasis-free survival (75 vs 65 %, p < 0.001) and breast cancer-specific survival (75 vs 69 %, p = 0.025) when compared to the younger series. In both old and the young, ductal cancers were associated with poor survival outcome when compared to non-ductal cancers. When compared to their younger counterparts, older patients with ductal type carcinomas had better metastasis-free and breast cancer-specific survival rates (their lower overall survival was likely to be due to death from other causes), despite having a lower likelihood of receiving adjuvant systemic therapy.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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.

A randomised trial of primary tamoxifen versus mastectomy plus adjuvant tamoxifen in fit elderly women with invasive breast carcinoma of high oestrogen receptor content: long-term results at 20 years of follow-up.

BACKGROUND: Long-term analysis of a randomised trial in Nottingham comparing tamoxifen versus surgery as initial treatment demonstrated that in oestrogen receptor (ER)-unselected cases, surgery achieved better local control, with no difference in overall survival. It was suggested that for patients with ER-rich tumours, local control and survival may be comparable. We now present long-term follow-up of a randomised trial designed to address this clinical scenario. PATIENTS AND METHODS: One hundred and fifty three fit elderly (≥70 years) women with clinically node-negative primary invasive breast carcinoma <5 cm of high ER content [histochemical (H) score ≥100] were randomised 2:1 to primary tamoxifen (Tam) (N = 100) or mastectomy with adjuvant tamoxifen (Mx + Tam) (N = 53). RESULTS: With median follow-up of 78 months, there was no statistically significant difference in 10-year rates of regional recurrence (9.0% versus 7.5%), metastasis (8.0% versus 13.2%), breast cancer-specific survival (89.0% versus 86.8%) or overall survival (64.0% versus 66.0%) between Tam and Mx + Tam; however, local control was inferior with Tam (local failure rates 43.0% versus 1.9%; P < 0.001). CONCLUSION: Irrespective of the degree of ER positivity, surgery achieved better local control. However, there was excellent and similar survival in both groups. Tam could be considered in those who are 'frail', refuse or prefer not to initially undergo surgery.

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

BACKGROUND: 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. METHODS: From 1973 to 2010, 1758 women were managed. Analysis was carried out based on retrospective review and continued update of patient records. RESULTS: 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]. CONCLUSIONS: 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.

Long-term clinical outcome of oestrogen receptor-positive operable primary breast cancer in older women: a large series from a single centre.

INTRODUCTION: A Cochrane review of seven randomised trials (N=1571) comparing surgery and primary endocrine therapy (PET) (oestrogen receptor (ER) unselected) shows no difference in overall survival (OS). We report outcome of a large series with ER-positive (ER+) early invasive primary breast cancer. METHODS: Between 1973 and 2009, 1065 older (≥ 70 years) women (median age 78 years (70-99)) had either surgery (N=449) or PET (N=616) as initial treatment. RESULTS: At 49-month median follow-up (longest 230 months), the 5-year breast cancer-specific survival (BCSS) and OS were 90 and 62%, respectively. Majority (74.2%) died from causes other than breast cancer. The rates (per annum) of local/regional recurrence (<1%) (following surgery), contralateral tumour (<1%) and metastases (<3%) were low. For patients on PET, 97.9% achieved clinical benefit (CB) at 6 months, with median time to progression of 49 months (longest 132 months) and significantly longer BCSS when compared with those who progressed (P<0.001). All patients with strongly ER+ (H-score >250) tumours achieved CB and had better BCSS (P<0.01). Patients with tumours having an H-score >250 were found to have equivalent BCSS regardless of treatment (surgery or PET; P=0.175), whereas for those with H-score ≤ 250, surgery produced better outcome (P<0.001). CONCLUSION: Older women with ER+ breast cancer appear to have excellent long-term outcome regardless of initial treatment. Majority also die from non-breast cancer causes. Although surgery remains the treatment of choice, patients with ER-rich (H-score >250) tumours tend to do equally well when treated by PET. This should be taken into account when therapies are considered.

A randomised trial of mastectomy only versus tamoxifen for treating elderly patients with operable primary breast cancer-final results at 20-year follow-up.

A recent Cochrane review of trials involving elderly women with operable primary breast cancer showed no significant difference in overall survival between surgery (±adjuvant tamoxifen) and primary endocrine therapy using tamoxifen. We report the final results of a randomised pilot trial comparing primary tamoxifen and wedge mastectomy as initial treatment in this population. One hundred and thirty-one women >70 years with early operable primary breast cancer (<5 cm), unselected for oestrogen receptor (ER), entered the trial in 1982-1987. Sixty-eight patients were allocated to tamoxifen only and 67 to wedge mastectomy only, as primary treatment. At 20 years of follow-up, the median time to local failure was significantly shorter in the tamoxifen arm though approximately one-fifth of patients in this group did not develop local failure requiring mastectomy. There was no difference in regional recurrence, distant metastases or overall survival between the mastectomy and tamoxifen arms. In this small study, primary endocrine therapy achieved local control in 30% of those surviving at 5 years and 20% at 10 years, unselected for ER. The primary therapy used did not significantly affect regional recurrence, incidence of distant metastases or overall survival. Primary endocrine therapy should certainly be considered in those patients with ER positive tumours and who are unfit (based on life expectancy) for or refuse surgery.