Efforts to combine endocrine and chemotherapy in the management of breast cancer: Do two and two equal three?

Abstract

Standard approaches to the systemic management of breast cancer have probably reached a plateau. Endocrine therapy leads to responses in only 1/3 of patients, probably even less if no clinical preselection is applied, and the median benefit probably does not exceed one year. Although three-drug chemotherapeutic combinations yield responses in 55-65% of patients, the median duration of response is at best only 10 months, and addition of more drugs does not seem to offer much additional benefit. Although combining these approaches seems attractive initially, the theoretical improvement would be modest even if the effects were additive, and in fact the endocrine component may well perturb the cell cycle kinetics to reduce sensitivity to the cytotoxic component so that results would be less than additive. Clinical trials of combined chemo-endocrine regimens have tended to evaluate only the initial response rate, whereas a valid comparison must consider the total response duration and survival given either combined or the usual sequential approaches. Combining endocrine and cytotoxic chemotherapies may have a greater effect when a more rational means for their amalgamation is employed. Early trials using endocrine manipulation to synchronize cell sensitivity to cytotoxic treatment have been promising. Increasing attention needs to be directed towards more innovative trial design which is respectful of the biological realities of cancer.

Divergent responses to epidermal growth factor in hormone sensitive and insensitive human prostate cancer cell lines

“…This transition is a major obstacle to successful treatment not only of carcinoma of the prostate but also in many other tumours originating from hormone responsive tissues (Hodges, 1979;Lippman, 1984 al., 1988;Traish & Wotiz, 1987;St-Arnaud et al, 1988). This complex relationship between steroid hormone and growth factors is not exclusive to the prostate gland, but has been observed in other hormone dependent organs.…”

“…This transition is a major obstacle to successful treatment not only of carcinoma of the prostate but also in many other tumours originating from hormone responsive tissues (Hodges, 1979;Lippman, 1984).…”

The nutritional herb Epimedium grandiflorum inhibits the growth in a model for the Luminal A molecular subtype of breast cancer

“…Patients with the molecular subtype Luminal A express estrogen receptor-α (ER)-α and progesterone receptor (PR), and they lack the expression of human epidermal growth factor receptor-2 (HER-2). Patients with this subtype respond to endocrine-based targeted therapy, such as selective ER modulators and specific small molecule inhibitors of estrogen biosynthesis (2)(3)(4). However, long-term endocrine-based therapy has been associated with adverse systemic toxicity, acquired tumor resistance and the emergence of drug resistant cancer stem cells that compromise therapeutic efficacy and promote disease progression (4)(5)(6).…”

“…However, the underlying molecular signaling pathways and targets that are responsible for the growth inhibitory effects of these herbs on breast cancer cells remain to be systematically elucidated. The human mammary carcinoma-derived cell line MCF-7 expresses ER-α and PR, and lacks HER-2 expression, thus representing an accepted pre-clinical cell model for the Luminal A molecular subtype of breast cancer (2)(3)(4). Previous studies using MCF-7 cells as a model for the Luminal A breast cancer subtype have demonstrated the direct growth inhibitory efficacy of extracts from Chinese nutritional herbs, such as LB and CO, that function through distinct mechanistic pathways (9,10).…”

Growth inhibition of estrogen receptor positive human breast cancer cells by Taheebo from the inner bark of Tabebuia avellandae tree

“…It is well recognized that ~80% of sporadic clinical breast cancers express estrogen receptor (ER) and that endocrine therapy with or without chemotherapy is a common treatment option (1,2). However, long-term treatment with chemoendocrine therapy is frequently associated with adverse toxicity that compromises patient compliance (3,4).…”