Balkees Abderrahman

Rethinking extended adjuvant antiestrogen therapy to increase survivorship in breast cancer

Extended adjuvant antiestrogen therapy1,2 with either tamoxifen or the aromatase inhibitor (AI)3 letrozole has improved survivorship in patients with breast cancer. Sledge and coauthors state, “it is arguable that antiestrogen treatments have had greater global impact than any other treatment intervention in cancer medicine.”4(p1981) This translational research strategy5 of continuing adjuvant therapy for up to a decade is now considered standard of care. Most importantly, early cessation of adjuvant antiestrogen therapy at 5 years, rather than continuing, increases the risk of recurrence in patients at high risk6 (those with large primary tumors and multiple positive axillary lymph nodes). Clearly, the fact that occult micrometastases have not been killed but remain dormant must now be addressed therapeutically. The advantage of antiestrogen therapy is low cost, but future barriers to combining antiestrogen therapy with precision medicines (palbociclib and everolimus) is the high cost of years of treatment when conventional long-term combination adjuvant therapy is used. Additionally, there will be increases in toxic effects over antiestrogen therapy alone. Both factors conspire to undermine patient adherence, which results in stopping treatment, recurrence, and death. The major benefit to patients of extended adjuvant antiestrogen therapy is the “carryover effect” that paradoxically continues to decrease recurrences for a decade once adjuvant antiestrogen therapy stops. The trial Adjuvant Tamoxifen Longer Against Shorter (ATLAS)1 compared 5 vs 10 years of adjuvant tamoxifen therapy. A significant decrease in mortality in favor of 10 years over 5 years of treatment only occurred when the analysis was done in years 10 to 15 after tamoxifen therapy was discontinued. Davies and coworkers1 note that compliance was 80% but calculated with full compliance using 10 years of tamoxifen strengthens the conclusion that mortality can be halved in the second decade. This carryover effect is linked7 to a woman’s own estrogen triggering apoptosis in a population of vulnerable micrometastases. It is perhaps time to formulate a preemptive salvage therapy designed to kill micrometastases during adjuvant therapy. We propose a new adjuvant strategy (Figure) focused specifically on high-risk patients with estrogen receptor (ER)-positive breast cancer.6 The Study of Letrozole Extension (SOLE)8 is a step in the right direction because it was designed to improve early decreases in mortality. The design exploits annual drug holidays so that a woman’s own estrogen triggers early estrogen-induced apoptosis. Patients who have already completed 5 years of adjuvant antiestrogen therapy were randomized to continuous letrozole for 5 years or letrozole for 4 years with an annual 3-month drug holiday. The fifth year is continuous letrozole therapy. It was hypothesized that the annual “cytotoxic purge” of endogenous estrogen would reduce the micrometastatic tumor burden, thereby preventing early recurrences in patients at high risk. No significant therapeutic benefit is noted in SOLE,8 so either longer pauses are required or low-dose estrogen needs to be administered. Most importantly, no harm is done by a 3-month drug holiday. Nevertheless, the results of SOLE8 are important for 2 reasons. First, patients who do not adhere to adjuvant AI therapy should be encouraged by physicians, and members of the breast cancer support team, to restart AI therapy after a pause. These pauses in SOLE are an advantage to patients because they create improvements in their quality of life. Looked at another way, SOLE is a planned nonadherence trial. Patients who resumed receiving the AI in SOLE after the drug holiday continued to benefit. By contrast, discontinuing adjuvant tamoxifen therapy completely after 1, 2, or 5 years results in early recurrence for short durations of adjuvant therapy. Second, the pause in adjuvant therapy proven to be safe in SOLE can now be used as a therapeutic window to treat highrisk patients. Micrometastases can be targeted with proven and effective US Food and Drug Administration (FDA)-approved precision medicines (Figure) to kill micrometastases. So how will the medicines be validated to treat breast cancer? A first step will be to screen combinations of effective precision medicines approved to treat any cancer. The test model initially will be long-term estrogendeprived (LTED) breast cancer cells in the laboratory.7 Strong survival pathways that produce resistance to estrogen-induced apoptosis will be identified and blocked. Effective medicine will be advanced for clinical validation. There has been considerable progress in identifying second-line therapies in metastatic breast cancer (MBC) following the failure of adjuvant AI therapy. By building on clinical knowledge with palbociclib and everolimus, additional FDA-approved precision medicines can be evaluated as combination therapies using the LTED MBC platform. Success at this stage not only improves the treatment of ER-positive LTED MBC but also predicts effectiveness as an adjuvant therapy. If there is one thing we learned about tamoxifen, it is that, used as a palliative in MBC at the end of life, it does not prevent death. The same drug used as a long-term adjuvant therapy after surgery, with the intervention of endogenous estrogen-induced apoptosis,7 decreases mortality.1,7 The high tumor burden of MBC limits tumor responsiveness. By contrast, the low tumor burden of micrometastatic disease aids patient benefit during adjuvant therapy. The efficacious cocktail proven in VIEWPOINT

Opportunities and challenges of long term anti-estrogenic adjuvant therapy: treatment forever or intermittently?

ABSTRACT Introduction: Extended adjuvant (5–10 years) therapy targeted to the estrogen receptor (ER) has significantly decreased mortality from breast cancer (BC). Areas covered: Translational research advanced clinical testing of extended adjuvant therapy with tamoxifen or aromatase inhibitors (AIs). Short term therapy or non-compliance increase recurrence, but surprisingly recurrence and death does not increase dramatically after 5 years of adjuvant therapy stops. Expert commentary: Compliance ensures optimal benefit from extended antihormone adjuvant therapy.Retarding acquired resistance using CDK4/6 or mTOR inhibitors is discussed. Preventing acquired resistance from mutations of ER could be achieved with Selective ER Downregulators (SERDs), eg fulvestrant. Fulvestrant is a depot injectable so oral SERDs are sought for extended use. In reality, a ‘super SERD’ which destroys ER but improves women’s health like a Selective ER Modulator (SERM), would aid compliance to prevent recurrence and death. Estrogen-induced apoptosis occurs in 30% of BC with antihormone resistance. The ‘one in three’ rule that dictates that one in three unselected patients respond to either hormonal or antihormonal therapy in BC occurs with estrogen or antiestrogen therapy and must be improved. The goal is to maintain patients for their natural lives by blocking cancer cell survival through precision medicine using short cycles of estrogen apoptotic salvage therapy, and further extended antihormone maintenance.

The modulation of estrogen-induced apoptosis as an interpretation of the women’s health initiative trials

The Women’s Health Initiative (WHI) consisted of two placebo controlled trials: one in women with a uterus, using conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) and the second trial in women without a uterus used CEE alone. The study population average age was approximately 63 years. Although the predicted rise in breast cancer occurred in the MPA plus CEE trial, the CEE alone trial, had a sustained decrease in breast cancer incidence. A unifying theory is presented that explains the decrease in breast cancer based on the new biology of estrogen-induced apoptosis in long-term estrogen deprived nascent breast cancer cells. Glucocorticoids block estrogen-induced apoptosis and MPA has glucocorticoid activity. This is why MPA increases breast cancer when used with CEE as menopausal hormone replacement. A safer menopausal hormone therapy can now be designed with a more selective synthetic progestin such as norethindrone acetate.

A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers

Prostate and breast cancer are the two cancers with the highest incidence in men and women, respectively. Here, we focus on the known biology of acquired resistance to antihormone therapy of prostate and breast cancer and compare laboratory and clinical similarities in the evolution of the disease. Laboratory studies and clinical observations in prostate and breast cancer demonstrate that cell selection pathways occur during acquired resistance to antihormonal therapy. Following sex steroid deprivation, both prostate and breast cancer models show an initial increased acquired sensitivity to the growth potential of sex steroids. Subsequently, prostate and breast cancer cells either become dependent upon the antihormone treatment or grow spontaneously in the absence of hormones. Paradoxically, the physiologic sex steroids now kill a proportion of selected, but vulnerable, resistant tumor cells. The sex steroid receptor complex triggers apoptosis. We draw parallels between acquired resistance in prostate and breast cancer to sex steroid deprivation. Clinical observations and patient trials confirm the veracity of the laboratory studies. We consider therapeutic strategies to increase response rates in clinical trials of metastatic disease that can subsequently be applied as a preemptive salvage adjuvant therapy. The goal of future advances is to enhance response rates and deploy a safe strategy earlier in the treatment plan to save lives. The introduction of a simple evidence-based enhanced adjuvant therapy as a global healthcare strategy has the potential to control recurrence, reduce hospitalization, reduce healthcare costs and maintain a healthier population that contributes to society.

Long-term adjuvant tamoxifen therapy and decreases in contralateral breast cancer

Tamoxifen revolutionized personalized medicine as the first targeted therapy proven to save lives in cancer.1 The paradigm change proposed to block the breast tumor estrogen receptor (ER), apply long-term adjuvant therapy to block estrogenstimulated recurrences,1,2 and apply the potential of tamoxifen to prevent breast cancer.3 These strategic recommendations were translated, during the past 3 decades, to clinical care.1 A meta-analysis4 of randomized clinical trials revealed that the strategic use of long-term adjuvant tamoxifen therapy is the key to therapeutic success. In addition, we now know that treating metastatic breast cancer (MBC) is only palliative at the end of life, but the same medicine saves lives if applied as long-term adjuvant therapy. Nevertheless, the question has to be asked whether the results would be the same outside the clinical trials process. The report in this issue of JAMA Oncology by Gierach and coworkers5 is reassuring because all the rules derived, until now, from randomized clinical trial overview analyses hold true.4 The authors5 performed a retrospective cohort study of contralateral breast cancer (CBC) in a population of 7541 patients from the records at Kaiser Permanente Northwest and Colorado from 1990 to 2008 and followed up through 2011. The median range of observation was 6.3 years, and 248 patients were identified to have developed CBC. Both tamoxifen and aromatase inhibitors reduced CBC, and longer adjuvant therapy proved to be more beneficial than shorter therapy. The authors5 estimate that 4 or more years of adjuvant tamoxifen therapy will prevent 3 CBCs per 100 women by 10 years after first diagnosis of ER-positive breast cancer. The authors5 stress that patients with breast cancer who are undergoing long-term adjuvant endocrine therapy should be encouraged to complete the full course. Indeed, this conclusion is even more important because in the future adjuvant endocrine therapy will last for 10 years.6,7 However, the challenge is adherence. Simply stated, no medicine, no benefit. A previous report8 calculates the number of deaths caused by nonadherence with adjuvant tamoxifen therapy. Low adherence results in early recurrence, increased medical costs, and a much worse quality of life.8 Gierach and coworkers5 report the persistence of the protective effects of adjuvant tamoxifen after treatment stops on CBC risk and that this effect is dependent on the duration of tamoxifen therapy. The authors5 cite a Danish study9 that found that current users of tamoxifen had a reduced risk of CBC,9 but former use of tamoxifen had no effect on CBC. Importantly, the adjuvant therapy used was only for a short period (median, 1-2.5 years).9 Persistence of the protective effects of tamoxifen using 5 years of treatment in high-risk populations is noted in the National Surgical Adjuvant Breast and Bowel Project trial9 to reduce the risk of primary breast cancer in high-risk women. These data9 are supported by the 96-month follow-up of the International Breast Cancer Intervention Study trial and the 20-year follow-up of the Royal Marsden Breast Cancer Prevention trial.10 The rule is clear: long-term treatment with tamoxifen (5 years) produces a sustained beneficial effect in preventing breast cancer, whereas short-term therapy does not. This clinical reality now presents the medical community with a paradox. Tamoxifen is a competitive inhibitor of estrogen action at the tumor ER. However, long-term adjuvant tamoxifen therapy1,2 must be continuous because failure of tamoxifen to block the tumor ER will result in recurrence. However, this laboratory strategy2 was not predictive for 5 years of adjuvant therapy. Patients survive without the benefit of tamoxifen blocking the ER to prevent recurrence. Herein lies the paradox. Tamoxifen is not cytotoxic, so where does the cytotoxicity of long-term tamoxifen therapy come from to protect patients after 5 years of adjuvant tamoxifen therapy? The answer comes from laboratory research on the evolution of acquired resistance to tamoxifen.11-13 Investigation of ER-positive breast tumors transplanted into tamoxifentreated ovariectomized athymic mice results in the development of acquired resistance to tamoxifen within 1 to 2 years.12 Uniquely, breast tumors develop because of tamoxifen treatment not despite tamoxifen treatment, and tumors use tamoxifen or estrogen to maintain tumor growth.12,13 This biological knowledge is the scientific foundation for using an aromatase inhibitor (to prevent the postmenopausal patient from synthesizing estrogen) or fulvestrant (which destroys the tumor ER as a pure antiestrogen) as second-line therapies for MBC in which tamoxifen treatment has not worked. Antiestrogenic therapy is the strategy of choice because estrogen stimulates tamoxifen-resistant tumor growth. Additional transplantation of ER-positive breast tumors with early acquired resistance to tamoxifen into tamoxifentreated athymic mice for up to 5 years replicates the clinical strategy of 5 years of adjuvant therapy.11 Tamoxifen-stimulated growth continues, but paradoxically physiologic estrogen has a significant antitumor effect.11 Estrogen is cytotoxic, and tumors disappear completely. Yao and coworkers11 proposed 2 clinical applications: (1) physiologic estrogen to treat MBC afRelated article Opinion

The First Targeted Therapy to Treat Cancer: The Tamoxifen Tale

The chance discovery of a new group of medicines called nonsteroidal anti-estrogens opened the door to new opportunities in therapeutics. Ethamoxytriphetol (MER25) was the first. However, based on studies in rats and mice, initial hopes were that nonsteroidal anti-estrogens would be new “morning after pills.” However, the discovery that clomiphene and tamoxifen induced ovulation in subfertile women would produce only a niche market in the 1960s. The treatment of metastatic breast cancer was an obvious choice as endocrine ablative surgery, i.e., oophorectomy, adrenalectomy, or hypophysectomy, was standard of care. Over a decade, in the 1970s, numerous nonsteroidal anti-estrogens were tested, but only tamoxifen went forward for the treatment of all stages of breast cancer, ductal carcinoma in situ, and male breast cancer and the reduction of risk for breast cancer in high-risk pre- and postmenopausal women.

A Novel Strategy to Improve Women’s Health: Selective Estrogen Receptor Modulators

Tamoxifen is the first selective estrogen receptor modulator. The extensive clinical and laboratory testing during the 1980s and 1990s raised questions about why there is target site specificity of tamoxifen in different species, i.e., tamoxifen is an estrogen in mice but a complete anti-estrogen in chicks. Additionally, tamoxifen has estrogen-like effects to lower circulating cholesterol, build postmenopausal bone in women, and stimulate the uterus and endometrial cancer growth but paradoxically prevents breast tumor growth. These observations lead to the SERM solution to prevent osteoporosis with a safe SERM but to prevent breast cancer at the same time. Raloxifene is the result with no increase in endometrial cancer incidence. There are now five FDA-approved SERMS available for use: tamoxifen, raloxifene, bazedoxifene, toremifene, and ospemifene. All have connections with discovery and basic research in Jordan’s laboratory.

Steroid Receptors in Breast Cancer

Abstract The estrogen receptor (ER) is the most important member of the nuclear receptor superfamily that controls the replication or apoptotic death of selected populations of breast cancer cells. The progesterone receptor is an estrogen-regulated protein in breast cancer that plays a role in predicting the hormone dependence of metastatic breast cancer. The mechanism of action of all effective antihormonal agents (tamoxifen, fulvestrant, aromatase inhibitors) is mediated through the ER signal transduction pathway and prevents estrogen action in the tumor cell. Tamoxifen is the pioneering selective ER modulator (SERM) that has estrogen-like effects in bone and the cardiovascular system, but antiestrogenic actions in breast cancer. The monthly depot injectable fulvestrant is a selective ER downregulator (SERD) that destroys the tumor ER and ERs throughout postmenopausal patients body. There is a current search for an orally active SERD.

Tamoxifen Decreases Mortality, but How?

TO THE EDITOR: Ekholm et al report that 2 years of adjuvant tamoxifen therapy in premenopausal patients with breast cancer significantly reduces cumulative breast cancer–related mortality from 10 to 25 years later. The strength of the small study was the use of the Swedish Cause of Death Register to monitor the South Swedish and South-East Swedish Breast Cancer Groups’ randomized phase III trial (SBII:2pre). No patients were lost to followup. This study adds to the knowledge gained from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trial that mortality profoundly decreases post-therapy and from the accumulated data from the Early Breast Cancer Trialists’ Collaborative Group. The authors’ conclusions also are consistent with all data on extended adjuvant tamoxifen in preand postmenopausal patients and aromatase inhibitors in postmenopausal patients. However, the facts derived from clinical trials need mechanistic explanations to enhance and improve patient care. Originally, tamoxifen was classified as a competitive inhibitor of estrogen action at the breast tumor estrogen receptor. Tamoxifen therapy initially was deployed as a palliative agent in metastatic breast cancer because it was not considered cytotoxic and therefore was not expected to save life as an adjuvant. Applications as an adjuvant therapy changed that view, but on the basis of evidence from a translational animal model, longer therapy was predicted to be superior to shorter therapy. The strategy to be translated to clinical trials was that continuous therapy was necessary to prevent estrogen from reactivating micrometastatic tumor growth. If estrogen reactivation of micrometastases occur, then this would guarantee recurrence and death. So, if mortality decreases after adjuvant tamoxifen therapy stops, just like with cytotoxic chemotherapy, where does the cytotoxicity of tamoxifen come from to save lives? The explanation has been deciphered in the laboratory, where acquired resistance was found to evolve over 5 years in estrogen receptor–positive tumor retransplantation into tamoxifen-treated athymic mice. Time is the key, and by coincidence, is a minimum of 5 years for the creation of enriched cell populations vulnerable to estrogen-induced apoptosis. It is proposed that once adjuvant therapy stops, a woman’s own estrogen destroys vulnerable cell populations by triggering apoptosis. Studies in cell culture have precisely described molecular mechanisms. Knowledge of the new biology of estrogen-induced apoptosis should now be leveraged strategically to control recurrence indefinitely. The aim is to achieve more cures with affordable interventions available to health care systems worldwide. Even only 2 years of adjuvant tamoxifen therapy in premenopausal patients with breast cancer creates some cures in breast cancer. The global goal must be to extend life expectancy from breast cancer by further controlling tumor recurrence.

t(9;22) as secondary alteration in core-binding factor de novo acute myeloid leukemia

The presence of specific recurrent karyotype abnormalities is one of the most powerful prognostic predictors in acute myeloid leukemia (AML). AML with inv(16) is categorized by the World Health Organization in the group of core-binding factors (CBF) AML, and it is associated with a favorable prognosis. From the molecular standpoint, the inv(16) leads to the formation of the CBFB-MYH11 fusion gene, which has a role in the disruption of normal hematopoiesis and in the inactivation of tumor suppressor genes needed for neoplastic transformation. Clonal evolution is generally considered a sign of disease progression in AML, but additional chromosomal aberrations seems not to impact on prognosis in CBF AML.