J.M. Dixon

The pharmacology of letrozole.

Recent clinical trials indicate that the third-generation aromatase inhibitors may be more effective than tamoxifen as first line endocrine therapy in ER+ metastatic breast cancer in postmenopausal women. This review will focus exclusively on the pharmacology of the non-steroidal inhibitor letrozole. Aromatase derived from a variety of sources is inhibited at low nM concentrations of the drug. In non-cellular systems, letrozole is 2-5 times more potent than anastrozole and exemestane in its inhibition of aromatase, whilst in cellular systems it is 10-20 times more potent. Anti-tumour effects of letrozole have been demonstrated in several animal models. In postmenopausal women, letrozole commonly suppresses circulating concentrations of estrone and estradiol to below the sensitivity limit of the assays used to measure them. In a recent randomized cross-over study, letrozole (2.5mg daily) achieved a significantly greater suppression of the plasma concentrations of both estrone and estrone sulphate than anastrozole (1mg daily) and a greater inhibition of in vivo aromatization. Letrozole appears to have a small effect on adrenal steroidogenesis such that a small number of patients exhibit an abnormal response to synthetic ACTH during letrozole therapy. This is unlikely to have any clinical significance. In short-term studies letrozole has been shown to increase markers of bone resorption indicating the need to monitor bone integrity when the drug is used for extended periods of time. A consistent effect of letrozole on serum lipids has not been demonstrated.

Invasive cribriform carcinoma of the breast

A histological review of 1003 invasive breast carcinomas identified 51 tumours in which the invasive component showed a predominantly cribriform pattern. These separated into two groups; 35 which showed exclusively cribriform or cribriform with a limited extent of tubular invasive elements only, designated ‘classical’ invasive cribriform carcinoma and 16 which also contained areas of less well differentiated invasive carcinoma, designated ‘mixed’ invasive cribriform carcinoma. At follow‐up, 10 to 21 years after diagnosis, none of the 35 patients with classical invasive cribriform carcinoma had died as a result of this initial carcinoma and 30 remained alive. Of the 16 remaining patients, whose tumours showed areas of less well differentiated carcinoma, only six remained alive. However, the adjusted 10 year survival rate of these patients in this mixed group was significantly better than that of invasive carcinoma in Edinburgh. Invasive cribriform carcinoma in its classical form, is a histological subgroup of invasive carcinoma with the same excellent prognosis as that of invasive tubular carcinoma.

ABC of Breast Diseases: Breast Cancer

Breast cancers are derived from the epithelial cells that line the terminal duct lobular unit. Cancer cells that remain within the basement membrane of the elements of the terminal duct lobular unit and the draining duct are classified as in situ or non-invasive. An invasive breast cancer is one in which there is dissemination of cancer cells outside the basement membrane of the ducts and lobules into the surrounding adjacent normal tissue. Both in situ and invasive cancers have characteristic patterns by which they can be classified. Carcinoma in situ affecting a breast lobule. The most commonly used classification of invasive breast cancers divides them into ductal and lobular types. This classification was based on the belief that ductal carcinomas arose from ducts and lobular carcinomas from lobules. We now know that invasive ductal and lobular breast cancers both arise from the terminal duct lobular unit, and this terminology is no longer appropriate. Some tumours show distinct patterns of growth and cellular morphology, and on this basis certain types of breast cancer can be identified. Those with specific features are called invasive carcinomas of special type, while the remainder are considered to be of no special type. This classification has clinical relevance in that certain special type tumours have a much better prognosis than tumours that are of no special type. #### Classification of invasive breast cancers Special types * Tubular * Cribriform * Medullary * Mucoid * Papillary * Classic Lobular No special type * Commonly known as NST or NOS (not otherwise specified) Useful prognostic information can be gained by grading such cancers Invasve carcinomas showing diffuse infiltration through breast tissue: grade I (left) II (centre), and grade III (right). Among the cancers of no special type, prognostic information can be gained by grading the degree of differentiation of the tumour. Degrees of glandular …

Pathological features of breast cancer response following neoadjuvant treatment with either letrozole or tamoxifen

Morphological characteristics, grading features, proliferation marker MIB1, apoptosis (by Tdt-mediated duTP-biotin nick-end labelling (TUNEL)), Bcl-2 expression, oestrogen receptor (ER) and progesterone receptor (PgR) status were compared in ER-positive breast cancers before and after 3 months of neoadjuvant therapy with either letrozole or tamoxifen. Daily treatment was with letrozole 2.5 mg (12 patients) or 10 mg (12 patients), or with tamoxifen 20 mg(24 patients). Letrozole treatment was associated with a pathological response in 17 of 24 (71%) patients. The predominant change in grading features was a decrease in mitosis, and the expression of MIB1 was reduced in all of the 22 evaluable cases. Whilst only marginal changes were observed in ER expression following letrozole therapy, PgR reactivity was reduced in 20 of 21 evaluable cases which were initially PgR-positive, becoming undetectable in 16 patients. Tamoxifen treatment was associated with pathological response in 15 of 24 (63%) tumours. In contrast to letrozole, the dominant change in grading feature was an increase in tubule formation, ER score was markedly reduced in most cases, and the most common effect on PgR was an increased expression. Following treatment with either tamoxifen or letrozole, variable effects were observed on the apoptotic index and expression of Bcl-2. These results indicate that both letrozole and tamoxifen have marked influences on the pathological features of breast cancer during neoadjuvant therapy. However, the effects of the two agents varied such that the phenotypes of letrozole- and tamoxifen-treated tumours differ markedly. Effects on clinical, pathological and biological endpoints were frequently disconcordant--future studies will therefore require the evaluation of multiple parameters in order to fully assess tumour response.

Breast cancer risk among the survivors of atomic bomb and patients exposed to therapeutic ionising radiation

Radiation induced breast cancer is a highly complex phenomenon, which most likely involves the accumulation of several genetic and epigenetic events. Studies of atomic bomb survivors, patients who underwent multiple fluoroscopic examinations during treatment for pulmonary tuberculosis, those who received therapeutic radiation for benign breast disease, such as acute post-partum mastitis, or those with an enlarged thymus or skin haemangioma and patients with Hodgkins disease treated by mantle radiotherapy established that the risk of breast cancer increases with exposure to ionising radiation. The carcinogenic effect of therapeutic or accidental radiation is highest when exposure occurs during childhood and exposure after age 40 imparts low or minimal risk. The risk of bilateral breast cancer is not significantly increased in the survivors of atomic bomb and therapeutic radiations. Fractionated exposures for therapeutic radiation are similar to a single exposure of the same total dose in their ability to induce breast cancer; this risk remains high for many years after exposure. Younger age at first full term pregnancy confers a protective effect against the risk of breast cancer in the survivors of atomic bomb but long-term data on this beneficial effect after therapeutic radiation is not available.

Neoadjuvant tamoxifen and aromatase inhibitors: comparisons and clinical outcomes

Neoadjuvant hormonal therapy for oestrogen receptor (ER) and/or progesterone receptor (PgR) positive large operable or locally advanced breast cancer is effective and a safe alternative to chemotherapy in postmenopausal women. A randomised trial has demonstrated that the response rate and the incidence and degree of downstaging with the aromatase inhibitor letrozole is significantly greater than with tamoxifen [J. Clin. Oncol. 19 (2001) 3808]. Tumours at all levels of ER appear to respond better to letrozole than tamoxifen but at low levels of ER responses are seen only with letrozole and not with tamoxifen. Patients most likely to benefit from neoadjuvant therapy and those who achieve the greatest reduction in tumour volume are those patients with tumours that express very high levels of ER (ALLRED category score 8). Both letrozole and anastrozole appear effective in both erbB2 positive and negative breast cancers. Three months of treatment is adequate to determine if a tumour will respond. Following breast-conserving surgery and radiotherapy, local recurrence rates appear satisfactory.

Neoadjuvant endocrine therapy of breast cancer: a surgical perspective

Neoadjuvant treatment with chemotherapy or endocrine agents is being used increasingly to downstage locally advanced and large operable breast cancers. Following these treatments, inoperable breast cancer often becomes fully resectable, and initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise neoadjuvant endocrine therapy: only patients with oestrogen receptor (ER)-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most. Such patients can expect a high probability of responses over a 3-month treatment period. Response to therapy should be monitored by clinical examination as well as by ultrasound, mammography, or other imaging procedures. Third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen in this treatment setting. In a large randomised trial of neoadjuvant endocrine therapy in postmenopausal women, letrozole achieved significantly higher response rates than tamoxifen, and a correspondingly higher rate of breast-conserving surgery was possible in the letrozole-treated patients. There is some evidence to suggest that the nature of the tumour response is different for preoperative endocrine therapy compared with chemotherapy. This difference may result in a higher rate of complete tumour excisions following breast-conserving surgery after neoadjuvant endocrine treatment. There appears to be a low rate of subsequent local recurrence in patients having breast-conserving therapy after neoadjuvant endocrine therapy.

Biological and clinical effects of aromatase inhibitors in neoadjuvant therapy.

Postmenopausal women with large primary oestrogen receptor-rich (>20 fmol/mg protein or 80 histoscore) breast cancers have been treated neoadjuvantly with either letrozole (2.5 or 10 mg daily n=12 in each case) or anastrozole (1 or 10mg daily n=12 and 11, respectively). Tumour was available for analysis before treatment (wedge biopsy) and 3 months later at definitive surgery (wide local excision or mastectomy). Clinical response to treatment was assessed by sequential measurements of tumour volume based on caliper assessment, ultrasound and mammography. Results showed that in these selected groups of patients a reduction in tumour volume with treatment was observed in 43 of 47 cases (91%). Pathological responses, i.e. clear decrease in tumour cellularity or increased fibrosis was evident in 32 cases (68%). Furthermore, there was a decrease with therapy in immunohistochemical staining for Ki67 in all tumours. Staining for progesterone receptor (PgR) was reduced in all 21 PgR-positive cancers treated with letrozole and in 16 of 17 positive cancers treated with anastrozole. These effects are at least as great as those seen in a non-randomised group of patients treated with tamoxifen over the same time period (additionally tamoxifen treatment was often associated with an increase in PgR staining). The results suggest that potent specific aromatase inhibitors will be valuable in treating hormone-dependent cancers.

ABC OF BREAST DISEASES - PROGNOSTIC FACTORS

Prognostic factors are of value for three main reasons: FIG Freedom from recurrence of cancer in patients in relation to age when breast cancer first diagnosed. (Proportional hazards model showed age <35 to have relative risk of 1.6 for distant disease.) Prognostic factors can be broadly classified into two groups: chronological factors, which are indicators of how long the cancer has been present and relate to stage of disease at presentation, and biological factors, which relate to the intrinsic or potential behaviour of the tumour. However, recent evidence suggests that age at diagnosis may also be a risk factor: younger women (aged under 35) have a poorer prognosis than older patients with cancer of equivalent stage. ### Chronological factors FIG Survival in relation to size of breast cancer. ### Tumour size The pathological size of a tumour correlates directly with survival; patients with smaller tumours have a better survival rate than those with large tumours. Maximum pathological size should be assessed in fresh specimens, and the size should be subsequently confirmed or amended after histological examination. Status of axillary lymph nodes The single best prognostic factor is the presence or absence of axillary nodal metastases. There is a direct correlation between survival and the number of axillary lymph nodes involved. ### Metastases Patients in whom cancer has spread beyond the axillary or internal mammary nodes (M1 or stage IV disease) have a much worse survival rate than patients whose disease is apparently localised. There are differences in survival between patients depending on the site of the metastatic disease, with patients who have supraclavicular involvement as their only site …

ABC of breast diseases. Metastatic breast cancer.

Few other cancers when they metastasise have such a variable natural course and effect on survival as breast cancer. Patients with hormone sensitive cancers may live for several years without any intervention other than various sequential hormonal manipulations. In contrast, patients with disease that is not hormone sensitive have a much shorter interval free of disease and shorter survival, reflecting the more aggressive biology of hormone independent cancers. The average period of survival after diagnosis of metastatic disease is 18-24 months, but this varies widely between patients. Clinical patterns of relapse predict future behaviour. Patients with a long interval without disease (more than two years) after primary diagnosis and favourable sites of recurrence (such as local lymph nodes and chest wall) survive longer than patients with either a short interval without disease or recurrence at other sites. Patients with visceral disease have the poorest outlook; these patients tend to have a short interval without disease and have cancers that are biologically more aggressive. FIG Median time of survival associated with sites of metastasis in patients with breast cancer. #### Hormonal treatment of metastatic breast cancer Premenopausal women Postmenopausal women Antioestrogens, aromatase inhibitors, and progestogens may be used in virtually any sequence in responsive patients. A patient may present with metastatic breast carcinoma or develop a systemic recurrence after treatment for an apparently localised breast cancer. The aim of treatment is to produce effective control of symptoms with minimal side effects. In terms of drug treatment this ideal is only achieved by hormonal treatment in the 30% of patients whose cancers respond to such drugs. There is …