Clinical, pathological, proliferative and molecular responses associated with neoadjuvant aromatase inhibitor treatment in breast cancer

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Abstract

Neoadjuvant treatment provides an exceptional setting in which to monitor clinical, pathological, proliferative and molecular responses to aromatase inhibitors. Sequential measurements of the primary tumour provide an accurate assessment of clinical changes and the relatively easy access to the tumour within the breast means that biopsies are available for histological and molecular measurements before and during treatment. Large randomised trials (P024 and IMPACT) together with informative non-randomised studies have demonstrated clinical responses to third generation aromatase inhibitors in 40–70% of ER-positive tumours, rates generally significantly higher than observed with tamoxifen. Pathological responses in terms of reduced cellularity/increased fibrosis are also seen in 65–75% of cases. Whilst these are more often seen in clinically responding tumours, the correlation between clinical and pathological response is not absolute. A marked feature of treatment with third generation inhibitors is a reduction in cellular proliferation. Using Ki67 as a marker, this may be observed as early as 10–14 days into treatment. Reduction in proliferation with treatment may be seen in both clinically responding and non-responding tumours, although incidence and degree of effect are higher in responding cases. Aromatase inhibitor treatment frequently fails to reduce proliferation in tumours over-expressing HER-2. In terms of molecular events, aromatase inhibitor treatment is associated with changes in expression of genes classically associated with oestrogen regulation (KIAA0101, ZWINT, IRS1 and TFF1) and cell cycle progression, most notably mitotic phase proteins (CDC2, CCNB1 and CKS2). Changes occur both in clinically responding and non-responding tumours. Although expression of no individual gene correlates absolutely with response status, expression signatures can be produced which distinguish between responding and non-responding tumours. In terms of gene ontology, terms relating to macro-molecular biosynthesis, translation and structural components of ribosomes are significantly enriched. Finally, molecular signatures can be used to illustrate the relative homogeneity of responding tumours and the disparate nature of non-responding tumours suggesting multiple and diverse pathways associated with resistance.

Introduction

Neoadjuvant treatment regimes in which aromatase inhibitors are given to patients with the primary tumour still within the breast provide excellent protocols by which to measure responses associated with therapy [1], [2], [3]. Firstly, clinical response may be accurately assessed by sequential measurement of the primary tumour. Additionally, because the cancer is invariably biopsied to confirm diagnosis and to determine oestrogen receptor (ER) status, tissue may be available to assess pathology, histology, proliferation and molecular phenotype/genotype and to relate these to clinical response. Because, in most protocols, patients come to definitive breast surgery after 3–4 months’ therapy, tumour is also available at this time and the effects of treatment may be measured on the same pathological and biological parameters. Experimental protocols have also been described in which additional biopsies have been taken after 10–14 days treatment so that early effects of therapy may be monitored and used to predict tumour response at 3–4 months [4], [5].

The paper reviews data derived from the neoadjuvant use of aromatase inhibitors in terms of observations on clinical, pathological and proliferative responses. It also describes how these interrelate, and may be used to understand the biological effects of aromatase inhibition in breast cancer and optimise patient management in those with the disease.

Section snippets

Clinical response

Clinical response rates for third generation aromatase inhibitors varies between 40 and 75% [3]. Two major clinical trials (P024 and IMPACT) have randomised neoadjuvant use of aromatase inhibitors versus tamoxifen [6], [7]. Benefits were greater for the aromatase inhibitors; in the P024 trial the difference was statistically significant (55% for letrozole versus 34% tamoxifen, p < 0.001) whereas that in IMPACT (anastrozole versus tamoxifen) did not reach statistical significance.

Pathological response

Marked changes in tumour morphology and histology may be associated with aromatase inhibitor treatment. In oestrogen receptor-rich tumours effects on histological features include changes in cellularity, degree of fibrosis and histological grading. These changes in tumour morphology may be seen by 3–4 months as evidenced by a clear reduction in cellularity or increase in fibrosis [8], [9]. Such pathological responses have been reported in 60–80% of tumours [10], [11], although complete

Proliferative response

Marked decreases in tumour proliferation (as evidenced by reduced mitotic score/staining of Ki67) in ER+ve breast cancers have been observed following treatment with aromatase inhibitors [10], [12]. These changes may be seen in about 80% of cases after 3 months’ treatment (with a median decrease of about 90%). As compared with neoadjuvant tamoxifen treatment the effects are generally more pronounced and seen in a greater proportion of cases [5], [10]. However, reduced proliferation may be

Molecular response

Clear evidence of molecular responses has been elicited following treatment with aromatase inhibitors. For example, the progesterone receptor (PgR) which is classically regarded as a marker of oestrogenic activity is clearly reduced in 70–80% of breast cancers and, in about one half of cases, it may completely disappear [12], [13]. Effects may be seen as early as 10–14 days and are consistent with the anti-oestrogenic effects of aromatase inhibitors. Loss of PgR expression may occur

Prediction of clinical response

Because markers of oestrogen action and cell proliferation are likely to be imperfect predictors of clinical response, it is important to identify novel genes or expression profiles which have a greater utility. To do this, microarrays from pre- and 14-day treatment tumour biopsies have been compared in patients either responding or resistant to neoadjuvant letrozole treatment [22], [24], [25]. Expression of no single gene correlated absolutely with response status. However, expression

Markers of resistance

Molecular studies may also be utilised to illustrate the relative heterogeneity of non-responding tumours [24], [26]. For example, using classical markers of oestrogen regulation such as KAA0101, SERPINA3, IRS1, TFF3, TFF1 and proliferation such as CDC, CKS2, cyclin B1, TYMS, PCNA, it is possible to subdivide tumours resistant to letrozole into three subgroups: (i) cases which are molecularly resistant both in terms of oestrogen markers and proliferation (a phenotype similar to the lack of gene

Conclusions

This review has illustrated how neoadjuvant treatment specifically using aromatase inhibitors presents a unique opportunity by which to assess the clinical, pathological, proliferative and molecular changes associated with this type of endocrine therapy in individual breast cancers. It is clear that whilst the different types of response are inter-related, there are relatively frequent discordant phenotypes where, for example, clinically responsive tumours fail to show pathological changes and

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