Simon Johnston

Fulvestrant - A Novel Endocrine Therapy for Breast Cancer

Fulvestrant is a novel endocrine therapy for breast cancer, with a unique structure and mode of action. It binds competitively to the oestrogen receptor (ER), with high affinity, and downregulates ER by functional blockade and increased turnover. Fulvestrant has reached the clinic via extensive pre-clinical and clinical trials, which demonstrated fulvestrants unique characteristics and showed that they translate to equivalent or improved clinical efficacy compared to established endocrine agents. Fulvestrant is currently licensed for use in postmenopausal women with hormone receptor positive advanced breast cancer which has progressed on prior endocrine therapy. As a pure oestrogen antagonist, fulvestrant avoids the risk of detrimental side effects of selective ER modulators such as tamoxifen, which has partial agonist activity. Fulvestrant, the only parenteral agent in this setting, has a good side effect profile and is well tolerated. Due to its unique mode of action, fulvestrant lacks cross-resistance with existing agents. Fulvestrant is the subject of much ongoing research, which utilises knowledge of its novel mechanism and pharmacokinetic profile in order to optimise clinical efficacy and explore new roles, including first-line use in advanced breast cancer, use in combination with existing agents, in males, and in premenopausal women, and use as an adjuvant therapy.

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.

The role of primary endocrine therapy in older women with operable breast cancer

A Cochrane review of randomized trials shows no difference in overall survival between surgery and primary endocrine therapy (PET) in older women with operable primary breast cancer. Most of these trials were small and unselected for estrogen receptor (ER) status. Evidence exists showing a significant correlation between the degree of ER-positivity and response and outcome in patients receiving PET. Although surgery remains the treatment of choice, patients with ER-rich tumors tend to do equally well on PET. When deciding optimal therapies, co-morbidities and frailty (which impact on the likelihood of death due to competing causes), patient choice, agent of choice (notably the third-generation aromatase inhibitors) and biology (more than just being ER-positive) should all be taken into account.

Current issues with luminal subtype classification in terms of prediction of benefit from endocrine therapy in early breast cancer

Endocrine therapy for oestrogen receptor‐positive (ER+) breast cancer (BC) is arguably the most successful targeted cancer therapy to date. Nevertheless, resistance to endocrine therapy still occurs in a significant proportion of patients, limiting its clinical utility. ER+ or luminal BC, which represents approximately three‐quarters of all breast malignancies, are biologically heterogeneous, with no distinct, clinically defined subclasses able to predict the benefit of endocrine therapy in early settings. To improve patient outcomes there is a clear need for improved understanding of the biology of the luminal BC, with subsequent translation into more effective methods of diagnosis to identify potential predictive biomarkers for endocrine therapy. This review summarises current knowledge of factors predictive of benefit of endocrine therapy and discusses why molecular classification systems of BC have yet to be translated into the clinic.

Endocrine Therapy for Breast Cancer: A Model of Hormonal Manipulation

Oestrogen receptor (ER) is the driving transcription factor in 70% of breast cancer. Endocrine therapies targeting the ER represent one of the most successful anticancer strategies to date. In the clinic, novel targeted agents are now being exploited in combination with established endocrine therapies to maximise efficacy. However, clinicians must balance this gain against the risk to patients of increased side effects with combination therapies. This article provides a succinct outline of the principles of hormonal manipulation in breast cancer, alongside the key evidence that underpins current clinical practice. As the role of endocrine therapy in breast cancer continues to expand, the challenge is to interpret the data and select the optimal strategy for a given clinical scenario.

Clinicopathological and prognostic significance of Ras association and pleckstrin homology domains 1 (RAPH1) in breast cancer

BackgroundRas association and pleckstrin homology domains 1 (RAPH1) is involved in cytoskeleton regulation and re-epithelialisation in invasive carcinoma and, therefore, may play a key role in carcinogenesis and metastasis. We, herein, investigated the biological and clinical significance of RAPH1 in breast cancer using large annotated cohorts.MethodsThe clinicopathological and prognostic significance of RAPH1 was assessed at the genomic and transcriptomic levels using The Cancer Genome Atlas (TCGA) dataset (n = 1039) and the results were validated using the Molecular taxonomy of breast cancer international consortium (METABRIC) cohort (n = 1980). RAPH1 protein expression was evaluated by immunohistochemistry in a large, well-characterised cohort of early-stage breast cancer (n = 1040).ResultsIn both the TCGA and METABRIC cohorts, RAPH1 mRNA expression and RAPH1 copy number alteration were strongly correlated. RAPH1 mRNA overexpression was significantly correlated with high expression of adhesion and EMT markers including CDH1, TGFβ1 and CD44. RAPH1 mRNA overexpression was a significant predictor of a poor prognosis (Hazard ratio 3.88; p = 0.049). High RAPH1 protein expression was associated with higher grade tumours with high proliferation index, triple negative phenotype and high E-cadherin expression. High RAPH1 protein expression was an independent predictor of shorter survival (Hazard ratio 4.37; p = 0.037).ConclusionsHigh RAPH1 expression is correlated with aggressive breast cancer phenotypes and provides independent prognostic value in invasive breast cancer.