Endocrine Therapy for Late-Stage and Metastatic Breast Cancer

Linking the Course of Advanced Breast Cancer to Female Reproductive Organs

In 1836 Sir Astley Cooper made one of the earliest known observations suggesting a role for endocrine therapy in treating breast cancer. He observed that advanced breast cancer appeared to wax and wane during a woman’s menstrual cycle. In 1889 Schinzinger proposed making younger women “older” by removing their ovaries, noting that younger women with breast cancer had more aggressive diseases than older women. In 1895 Beatson extended this rationale into the arena of cancer treatment by performing a bilateral oophorectomy on a woman who had developed recurrent breast cancer involving the chest wall 6 months after mastectomy. He reported that her chest wall disease resolved within 8 months of the bilateral oophorectomy, and the patient remained disease-free for 4 years. Boyd subsequently reported a series of 54 patients who underwent bilateral oophorectomy as a treatment for advanced breast cancer. Approximately one-third of patients had tumor regression and improved overall survival (OS). This ushered in an era of oophorectomy to treat advanced breast cancer.

Recognizing Hormone Dependency for Certain Human Tumors

Huggins and Bergenstal reported the beneficial effects of orchiectomy in men with prostate cancer. Subsequently, Huggins and Hodges showed that the effect of orchiectomy was mediated by reducing testosterone levels. Block and colleagues contributed by demonstrating that the basal level of estrogen production was not reached for several months after ovarian radiation, correlating with the fact that breast cancers often did not regress until several months after ovarian radiation. When synthetic corticosteroids became available in the early 1950s, bilateral surgical adrenalectomy also became feasible as a means of removing other sources of steroid hormones. In an early report by Huggins and Bergenstal, three of six patients with advanced breast cancer appeared to benefit from bilateral adrenalectomy. Other investigators subsequently demonstrated objective response rates of 30% to 40% in advanced breast cancer patients after bilateral adrenalectomy.

Understanding Estrogen Action and Developing Antiestrogens

Modern drug development originated with the pioneering studies of Dodds and colleagues in the 1930s and their discovery of the nonsteroidal estrogen diethylstilbestrol (DES). In 1944 Haddow and colleagues observed that women with advanced breast cancer responded to high-dose estrogen. The women who responded tended to be older, but it was unclear why only some women responded to endocrine therapy. Similarly, responses to bilateral adrenalectomy had been noted to occur in premenopausal women who had previously responded to oophorectomy. Manipulation of female hormone levels was clearly successful in certain populations, but insight into the mechanism was lacking.

This clinical observation was correlated with the mechanism when Jensen and Jacobson observed that radiolabeled estradiol localized to estrogen target tissues such as the uterus, vagina, and pituitary gland. They proposed that a receptor must be present in these tissues to regulate response to estradiol. The estrogen receptor (ER) was subsequently identified. ER assays were then developed to predict which breast cancer patients would respond to endocrine therapy. The response rate to endocrine therapy was 30% to 40% in unselected patients, compared with 60% or more in women with a positive ER assay.

In 1958 Lerner and colleagues reported the biological properties of the first nonsteroidal antiestrogen, MER-25. The compound was found to be an antiestrogen in all species tested. MER-25 was initially studied as a contraceptive in laboratory animals. Unfortunately, the large doses needed for MER-25 to work were associated with unacceptable central nervous system side effects. A successor compound, MRL-41, or clomiphene, was a more potent antiestrogen and an effective antifertility drug in animals, although it paradoxically induced ovulation in subfertile women. Clomiphene demonstrated modest activity in the treatment of advanced breast cancer, but further development stopped after the introduction of tamoxifen.

The Modern Era of Endocrine Therapy

Similar to clomiphene, Harper and Walpole demonstrated that tamoxifen, a selective estrogen receptor modulator (SERM), had antiestrogenic and antifertility properties. Tamoxifen was evaluated in several clinical scenarios, including as a contraceptive. The first successful use of tamoxifen in treating advanced breast cancer was reported in 1971, with 10 of 46 patients (22%) demonstrating responses to therapy. The response rates were similar to those with DES; however, side effects were significantly less with tamoxifen. Thus, tamoxifen became the endocrine therapy of choice for advanced breast cancer in the 1970s. In 1986, tamoxifen was approved for adjuvant treatment of postmenopausal women with node-positive breast cancer. In 1990 tamoxifen was approved as an adjuvant treatment for pre- and postmenopausal women with node-negative disease.

Hormone Assays

Approximately two-thirds of breast cancers express female hormone receptors (HRs): ER and/or progesterone receptor (PR). The decision to choose one endocrine therapy over another must consider the comparative efficacy, the ease of administration, the potential toxicity of therapy, and the menopausal status of the patient. There are multiple techniques available for determining the ER and PR status of tumors. ER can be measured using a ligand-binding method after isolation from the tumor sample. This method has multiple shortcomings, including expense, fresh frozen tissue requirement, and radioactive reagents. The development of monoclonal antibodies specific to ER and PR and immunohistochemistry (IHC) techniques provided an alternative means of determining ER/PR status. IHC is currently the most commonly used technique for assessing ER and PR status and overcomes many of the problems associated with ligand-binding assays. One of the challenges of IHC is that the results are subjective and do not adequately quantitate the level of ER or PR expression. Newer techniques, such as reverse transcriptase-polymerase chain reaction (PCR), tissue microarrays, and nanotechnology, are being investigated as alternatives to IHC, with improved ER and PR levels quantitation.

Predictive Power of HR Status

The HR status of a tumor determines the likelihood that a patient will respond to endocrine therapy. The very early studies assessing the predictive value of HR showed that 75% to 80% of patients with breast tumors positive for both ER and PR will respond to initial endocrine therapy. The response rates to endocrine therapy are lower for ER-positive/PR-negative tumors and ER-negative/PR-positive tumors, at 25% to 30% and 40% to 45%, respectively. Endocrine therapy may provide significant benefit in breast cancer with at least 1% tumor cells positive for ER and/or PR. Thus, current ASCO/CAP guidelines define a breast cancer with at least 1% tumor cells positive for ER and/or PR as ER and/or PR-positive breast cancer. The level of HR expression in breast cancer is predictive of greater objective response and clinical benefit with endocrine therapy. Patients whose tumors do not express either ER or PR typically do not benefit from endocrine therapy. However, there can be concerns about false negativity of the assays, especially when evaluating ER and PR status from a bone biopsy.

Selective Estrogen Receptor Modulators