L. Winterbottom

Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer.

The progesterone receptor antagonist, Onapristone, is an effective endocrine agent in experimental breast cancer models. This study aimed to investigate this agent as first-line endocrine therapy in patients with breast cancer. However, owing to the recognition in this and other clinical studies that some patients on Onapristone developed liver function test abnormalities, the development of this drug and recruitment to the study stopped in 1995. 19 patients either with locally advanced breast cancer (n = 12) or who were elderly, unfit patients with primary breast cancer (n = 7) received Onapristone 100 mg/day. Seventeen of the 19 tumours expressed oestrogen receptors (ER) whilst 12 of the 18 tumours tested expressed progesterone receptors (PgR). Tumour remission was categorised by International Union Against Cancer criteria. One patient was withdrawn after 4.5 months while her disease was static. Of the remaining 18 patients, 10 (56%) showed a partial response and 2 (11%) durable static disease (> or = 6 months), giving an overall tumour remission rate of 67%. The median duration of remission was 70 weeks. Transient liver function test abnormalities developed in a number of patients, mainly during the first 6 weeks of treatment. In conclusion Onapristone can induce tumour responses in human breast cancer.

Suppression of ovarian function in combination with an aromatase inhibitor as treatment for advanced breast cancer in pre-menopausal women

Trials have shown superiority of aromatase inhibitors (AIs) over tamoxifen for post-menopausal oestrogen receptor-positive advanced breast cancer (ER+ABC). We previously reported the use of goserelin plus anastrozole (G+A) as second-line endocrine therapy for pre-menopausal ER+ABC. We report clinical and endocrine data from G+A as first-line systemic therapy. Thirty-six patients (median age=44 years) with metastatic (N=28) and locally advanced disease were administered G+A for ≥6 months (unless progressed prior). Some (N=13) received further therapy with goserelin plus another AI (steroidal), exemestane (G+E). Serial serum hormone assays (oestradiol, dehydroepiandrosterone sulphate, testosterone, follicle stimulating hormone and luteinising hormone) were performed. Twenty-four patients (67%) derived clinical benefit (CB) (5% complete response, 31% partial response, 31% stable disease for ≥6 months) with median time to progression and duration of CB of 12 (2-47) and 24+(7-78+) months respectively. Ten patients were still receiving first-line G+A at analysis. Amongst 13 patients who went onto receive G+E, 38% achieved CB with a mean duration of 13+(7-32) months. Therapy was well tolerated with no withdrawals. The combination of G+A resulted in 98% reduction (from pre-treatment to 6-month) in median levels of oestradiol (from 574.5 pmol/L; inter-quartile range (IQR)=209-1426; (N=6) to 13.45 pmol/L; IOQ=5.5-31.5 (N=4) whilst the levels of other hormones had minimal fluctuations during therapy. The combinations of ovarian function suppression (using G) and AIs produce sustained CB and minimal side effects in pre-menopausal ER+ABC with significant reduction in oestradiol levels. Within the limitations of being a non-randomised study, they should be considered in appropriate patients with hormone-sensitive ABC.

Early primary breast cancer in the elderly - pattern of presentation and treatment.

INTRODUCTION The incidence of primary breast cancer in elderly patients is increasing. However, little is known about their biological profile and most appropriate clinical management, as most studies have been conducted in the younger population. This study aimed to identify a profile of characteristics in elderly women with operable primary breast cancer and investigate the dynamics influencing the treatment decision-making process. METHODS A review of 268 consecutive female patients >70 years of age, diagnosed with early operable primary breast cancer (<5 cm) over a 30-month period at the Nottingham Breast Institute, was conducted. Age, co-morbidity, cancer characteristics, treatment offered and undertaken, and reason for patient choice were recorded and analysed. RESULTS The median age was 78 (range 70-100) years. In our study, 82% of the patients had one or more co-morbidities, with 34% of them having three or more co-morbidities. The commonest pathological diagnosis (from needle core biopsies) was invasive ductal carcinoma of no special type (76%) with histological grade 2 (64%). Majority of them were oestrogen receptor (ER)-positive (84%) and had a high histochemical (H)-score (83% with H-score >200). Most of the patients (60%) underwent primary surgical management, of which 45.4% received breast-conserving surgery. Among the patients who had breast-conserving surgery, 68% of them received adjuvant radiotherapy. When offered genuine choice in treatment options, most patients chose non-operative treatment. Patients who underwent non-operative treatment were on average seven years older and had significantly more co-morbidities than those who had surgery. CONCLUSION The elderly population evidently have demographic and cancer characteristics distinct from their younger counterparts, with less patients receiving surgical management. Further work is underway to correlate this with their clinical outcomes and to examine the factors behind the treatment decision-making process.

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.

Comprehensive geriatric assessment for older women with early breast cancer – a systematic review of literature

BackgroundThe Comprehensive Geriatric Assessment (CGA) is an analytical tool increasingly implemented in clinical practice. Breast cancer is primarily a disease of older people; however, most evidence-based research is aimed at younger patients.MethodsA systematic review of literature was carried out to assess the use of CGA in older breast cancer patients for clinical decision making. The PubMed, Embase and Cochrane databases were searched.ResultsA total of nine useful full text article results were found. Only five of these were exclusively concerned with early breast cancer; thus, studies involving a variety of cancer types, stages and treatments were accepted, as long as they included early breast cancer.The results comprised a series of low sources of evidence. However, all results shared a common theme: the CGA has a use in determining patient suitability for different types of cancer treatment and subsequently maximizing the patient’s quality of life.ConclusionsThere is not yet sufficient high level evidence to instate CGA guidelines as a mandatory practice in the management of breast cancer, due to the heterogeneity of available studies. More studies need to be conducted to cement current work on the benefits of the CGA. An area of particular interest is with regard to treatment options, especially surgery and chemotherapy, and identifying patients who may be suitable for these treatments.

Biological profile of oestrogen receptor positive primary breast cancers in the elderly and response to primary endocrine therapy

Aromatase inhibitors have been shown to be superior to Tamoxifen in several settings. It is unclear whether this superiority extends to their use as primary endocrine therapy in elderly patients with early operable primary breast cancer. Biological characteristics of the tumours may aid in selecting the most suitable agent. Primary endocrine therapy with Anastrozole in 64 women >70 years with oestrogen receptor alpha-positive (ERalpha+) breast cancer was compared to that in 84 treated with Tamoxifen during the same period. Biomarkers were assessed by immunohistochemistry on diagnostic core biopsies. There was no significant difference between the two groups (Anastrozole vs Tamoxifen) in terms of clinical benefit rates at 6 months (97% vs 100%) or median progression free survival (16.5 vs 22.5 months). There were no withdrawals due to adverse events from Anastrozole, compared to four with Tamoxifen. 46%, 99%, 8% and 5% of all patients were positive for progesterone receptor, ERbeta2, HER2 and EGFR, respectively, and 64% of patients had a moderate Ki-67 index. Positive HER2 status (18 vs 21 months, p=0.003) and moderate Ki-67 index (17.5 vs 23 months, p=0.042) were associated with significantly shorter progression free survival. Results thus far show that primary endocrine therapy with Anastrozole in elderly patients with early operable ERalpha+ breast cancer is similar to Tamoxifen in terms of efficacy, but appears to be associated with less adverse events leading to withdrawals. In this population, ERalpha+ breast cancer also appears to have a less aggressive biological profile favouring better hormone sensitivity.

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.

OBJECTIVES 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). MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.

Care of the older woman with primary breast cancer: a sign of the times?

POROCK D., CHEUNG, K.L., MORGAN D.A.L., WINTERBOTTOM L., RICHARDSON H. & ELLIS I.O. (2009) European Journal of Cancer Care18, 527–529 Care of the older woman with primary breast cancer: a sign of the times?