The St. Gallen Prize Lecture 2011: evolution of long-term adjuvant anti-hormone therapy: consequences and opportunities

Abstract

The successful translation of the scientific principles of targeting the breast tumour oestrogen receptor (ER) with the nonsteroidal anti-oestrogen tamoxifen and using extended durations (at least 5 years) of adjuvant therapy, dramatically increased patient survivorship and significantly enhanced a drop in national mortality rates from breast cancer. The principles are the same for the validation of aromatase inhibitors to treat post-menopausal patients but tamoxifen remains a cheap, life-saving medicine for the pre-menopausal patient. Results from the Oxford Overview Analysis illustrate the scientific principle of "longer is better" for adjuvant therapy in pre-menopausal patients. One year of adjuvant therapy is ineffective at preventing disease recurrence or reducing mortality, whereas five years of adjuvant tamoxifen reduces recurrence by 50% which is maintained for a further ten years after treatment stops. Mortality is reduced but the magnitude continues to increase to 30% over a 15-year period. With this clinical database, it is now possible to implement simple solutions to enhance survivorship. Compliance with long-term anti-hormone adjuvant therapy is critical. In this regard, the use of selective serotonin reuptake inhibitors (SSRIs) to reduce severe menopausal side effects may be inappropriate. It is known that SSRIs block the CYP2D6 enzyme that metabolically activates tamoxifen to its potent anti-oestrogenic metabolite, endoxifen. The selective norepinephrine reuptake inhibitor, venlafaxine, does not block CYP2D6, and may be a better choice. Nevertheless, even with perfect compliance, the relentless drive of the breast cancer cell to acquire resistance to therapy persists. The clinical application of long-term anti-hormonal therapy for the early treatment and prevention of breast cancer, focused laboratory research on the discovery of mechanisms involved in acquired anti-hormone resistance. Decades of laboratory study to reproduce clinical experience described not only the unique mechanism of selective ER modulator (SERM)-stimulated breast cancer growth, but also a new apoptotic biology of oestradiol action in breast cancer, following 5 years of anti-hormonal treatment. Oestradiol-induced apoptotic therapy is currently shown to be successful for the short-term treatment of metastatic ER positive breast cancer following exhaustive treatment with anti-hormones. The "oestrogen purge" concept is now being integrated into trials of long-term adjuvant anti-hormone therapy. The Study of Letrazole Extension (SOLE) trial employs "anti-hormonal drug holidays" so that a woman's own oestrogen may periodically purge and kill the nascent sensitized breast cancer cells that are developing. This is the translation of an idea first proposed at the 1992 St. Gallen Conference. Although tamoxifen is the first successful targeted therapy in cancer, the pioneering medicine is more than that. A study of the pharmacology of tamoxifen opened the door for a pioneering application in cancer chemoprevention and created a new drug group: the SERMs, with group members (raloxifene and lasofoxifene) approved for the treatment and prevention of osteoporosis with a simultaneous reduction of breast cancer risk. Thus, the combined strategies of long-term anti-hormone adjuvant therapy, targeted to the breast tumour ER, coupled with the expanding use of SERMs to prevent osteoporosis and prevent breast cancer as a beneficial side effect, have advanced patient survivorship significantly and promise to reduce breast cancer incidence.

Fig. 1

The structure of medicines and compounds mentioned in the text. Oestradiol and diethylstilboestrol are oestrogens, whereas all others are selective oestrogen receptor modulators (SERMs) used in medicine for the treatment and chemoprevention of breast cancer (tamoxifen), treatment and prevention of osteoporosis and the chemoprevention of breast cancer (raloxifene). The new SERM, lasofoxifene, is approved for the treatment and prevention of osteoporosis in the European Union.

Fig. 2

The metabolic activation of tamoxifen with a low affinity to the tumour oestrogen receptor by the P₄₅₀ enzyme CYP2D6 enzyme to endoxifen with a high affinity for the tumour oestrogen receptor.

Fig. 3

The metabolism of tamoxifen to 4-hydroxytamoxifen, a metabolite with a high affinity for the oestrogen receptor. Tamoxifen’s major metabolite is N-desmethyltamoxifen that has a similar binding affinity to the oestrogen receptors as tamoxifen. However, N-desmethyltamoxifen is metabolically activated to endoxifen, with a high binding affinity for the oestrogen receptor. The selective serotonin re-uptake inhibitors (SSRIs), paroxetine and fluoxetine block the metabolic activation of tamoxifen by blocking CYP2D6. Venlafaxine, a selective norepinephrine re-uptake inhibitor (SNRI), does not affect tamoxifen’s metabolic activation, and therefore is the preferred choice to treat menopausal symptoms experienced with tamoxifen.

Fig. 4

The development of acquired antihormone resistance to selective oestrogen receptor modulators (SERMs) (tamoxifen or raloxifene). The unique feature of Phase I antihormone resistance is that oestrogen receptor positive breast tumours grow in response to either physiological oestradiol or the SERM. In the clinical setting (and laboratory models), an aromatase inhibitor (no oestrogen) or the pure anti-oestrogen, fulvestrant, that destroys the oestrogen receptor, stops the growth of Phase I resistant tumours to tamoxifen.

Fig. 5

Diagrammatic representation of the actions of physiologic oestradiol (E2) on the growth of small phase II MCF-7 tamoxifen resistant tumors in ovariectomized athymic mice. A larger tumour will regress with oestradiol treatment but will eventually display oestrogen-stimulated growth. If tumours are re-transplanted into a new generation of ovariectomized athymic mice and treated with oestradiol, tamoxifen will block oestrogen-stimulated tumour growth. First presented in St. Gallen, 1993.

Fig. 6

The evolution of drug resistance to SERMs. Acquired resistance occurs during long-term treatment with a SERM and is evidenced by SERM-stimulated breast tumour growth. Tumours also continue to exploit oestrogen for growth when the SERM is stopped, so a dual signal transduction process develops. The aromatase inhibitors prevent tumour growth in SERM-resistant disease and fulvestrant that destroys the ER is also effective. This phase of drug resistance is referred to as Phase I resistance. Continued exposure to a SERM results in continued SERM-stimulated growth (Phase II), but eventually autonomous growth occurs that is unresponsive to fulvestrant or aromatase inhibitors. The event that distinguishes Phase I from Phase II acquired resistance is a remarkable switching mechanism that now causes apoptosis, rather than growth, with physiologic levels of oestrogen. A similar evolution occurs with aromatase inhibitor resistance from oestrogen independent growth with a transition to oestrogen-induced apoptosis. These distinct phases of laboratory drug resistance have their clinical parallels and this new knowledge is being integrated into the treatment plan.

Fig. 7

The non-canonical pathway results in the activation of IKKα by NIK and phosphorylation of the NF-κB subunit. This process results in the conversion of p100 to p52. It is the p52-RelB heterodimers that target distinct κB elements on DNA. ANK (ankyrin-repeat motifs). NIK (NF-κB kinase). RelB (NF-κB family member). RHD (Rel-homology domain). TAD (transcriptional activation domain).

Fig. 8

The reversal of oestradiol-induced apoptosis (1 nM) by increasing concentrations of 4-hydroxytamoxifen or endoxifen. This nonsteroidal antioestrogen effect highlights the ER dependence for oestradiol-induced apoptosis.

Fig. 9

The Schema for the Study of Letrozole Extension (SOLE) conducted by the International Breast Cancer Study Group (IBCSG 35-07). Patients randomized following five years of adjuvant antihormone therapy to letrozole continuously or intermittent letrozole (3 month drug holidays per year for 5 years). The rationale is that the woman’s own oestrogen in the intermittent arm will trigger apoptosis in aromatase inhibitor resistant cells and reduce recurrence rates.

Fig. 10

The evolution of drug resistance and rapid alterations in cell populations if a c-Src inhibitor PP2 (5 μM) is incubated with MCF-7:5C cells in the presence of 1 nM oestradiol for two months to mimic a clinical scenario of a postmenopausal woman who fails an aromatase inhibitor to block growth. Apoptosis from oestrogen is blocked and the cells revert to Phase I resistance, i.e. oestrogen and SERM-stimulated growth.