Tamoxifen In Postmenopausal Patients Research Articles

IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer.

Preclinical studies indicate that activated IGF‐1R can drive endocrine resistance in ER‐positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF‐1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF‐1R‐mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF‐1R, p‐IGF‐1R/InsR, p‐ERα(Ser118), p‐ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p‐IGF‐1R/InsR and PI3K/MAPK pathway activation in MCF‐7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth‐stimulating and ‐inhibiting conditions. Patients with ER+, IGF‐1R‐positive breast cancer without p‐IGF‐1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p‐IGF‐1R/InsR‐positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p‐ERα(Ser118) or p‐ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF‐7 cells, IGF‐1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF‐1R overexpression. This could be abrogated by the dual IGF‐1R/InsR inhibitor linsitinib, but not by the IGF‐IR‐selective antibody 1H7. In MCF‐7 and T47D cells, stimulation of the IGF‐1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p‐IGF‐1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF‐1R is driving tamoxifen resistance to be abrogated by linsitinib.

Abstract P5-04-15: Enhancing response to estrogen therapy in ER+ breast cancer with novel scheduling and dosing regimens

Abstract Estrogen therapy was historically used as a standard breast cancer treatment from the 1940s until the introduction of tamoxifen in the 1970s. Although a clinical trial directly comparing the synthetic estrogen diethylstilbestrol and tamoxifen in post-menopausal patients demonstrated no significant difference in progression-free survival between the two, tamoxifen showed a more favorable toxicity profile and estrogens fell out of favor. However, 1 in 3 patients eventually recur and develop advanced disease that is resistant to all available anti-estrogens. Estrogen therapy is being resurrected in clinical trials for advanced, heavily pre-treated ER+ breast cancer. These studies demonstrate that ˜30% of patients respond to treatment with estrogens. However, little pharmacologic work has been done to optimize the schedule and method of hormone delivery. Estrogen therapies such as 17b-estradiol (E2) and ethinylestradiol are typically administered orally several times daily. Toxicities have been observed with such regimens, and there is no evidence that the maximally efficacious doses or schedules are being used clinically. We used two in vivo tumor models to preclinically define the optimal dosing schedule and method of E2 delivery that maximizes response. WHIM16 patient-derived ER+ breast cancer xenografts (PDX) and C7-2-HI ER+ murine mammary adenocarcinoma allografts both grow in ovariectomized (“estrogen-deprived”) mice, and regress in response to E2 treatment. We tested an array of E2 doses and delivery methods [e.g., oral gavage, subcutaneous (s.c.) injection, s.c. pellet, and s.c. osmotic pump] in mice bearing C7-2-HI and WHIM16 tumors to determine optimal methods for inducing maximal and sustained tumor regression. We found that oral dosing is less effective at inducing tumor regression than other methods. However, intermittent high-dose estrogen given as 1 mg of E2 orally every 14 days both prevented tumor growth and did not result in toxicity, suggesting that intermittent dosing should be further examined as a means to increase therapeutic index. Although estrogen therapy induces clinical response in a subset of patients with ER+ disease, nearly all patients eventually experience disease progression and develop resistance to the therapeutic effects of estrogen. Clinical observations suggest that some cancers that progressed on estrogen therapy are re-sensitized to anti-estrogen treatment. We therefore examined whether resistance to estrogen therapy could be prevented by preemptively cycling estrogen therapy with estrogen deprivation in mice. Discontinuous scheduling of E2 and estrogen deprivation was tested with either 1 or 4 weeks on E2 treatment, followed by estrogen deprivation until tumors re-grew to baseline volume, then E2 treatment was repeated. In the WHIM16 tumor model, the 4-week E2 treatment cycle nearly doubled time to recurrence compared to mice treated continuously with E2. Surprisingly, there was no difference in time to recurrence between groups treated with the 1-week cycle vs. continuous E2. However, tumors that re-grew on continuous E2 were sensitized to estrogen deprivation. These collective findings warrant clinical testing of schedules of alternating estrogen and anti-estrogen therapies. Citation Format: Traphagen NA, Hosford SR, Miller TW. Enhancing response to estrogen therapy in ER+ breast cancer with novel scheduling and dosing regimens [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-15.

Abstract P2-09-16: How population-based data complement trial data in the adjuvant endocrine treatment of ER+/HER2+ breast cancers

Abstract Background This study is part of the Netherlands Breast Cancer Project, initiated to address research questions that are unlikely answered by future randomized controlled trials (RCT). Here we investigated whether aromatase inhibitors (AI) are superior over tamoxifen (TAM), in the treatment of Estrogen Receptor (ER) positive Human Epidermal growth factor Receptor 2 (HER2) positive breast cancer, using treatment and outcome data from the population based Netherlands Cancer Registry (NCR). RCTs showed superiority of AI over TAM in postmenopausal ER+/HER2+ patients while a (non-significant) suggestion for worse outcome was observed among premenopausal patients treated with AI in the SOFT/TEXT trial. Perimenopausal women were not considered in these trials. Methods Dutch women without a prior malignancy, diagnosed between 2005-2007 with an ER+/HER2+, endocrine treated, non-metastatic, invasive breast cancer, were identified through the NCR and followed until 2013. Since data on menopausal status were lacking, we used age at diagnosis as a proxy to categorize patients as premenopausal (≤45 years), perimenopausal (45-55 years) and postmenopausal (>55 years). A time-dependent variable was calculated indicating whether AI treatment was given for >50% (denoted AI treated) vs. <50% (denoted TAM treated) of endocrine treatment duration. Recurrence-free survival (RFS) and overall survival (OS) were assessed using an extended Kaplan-Meier survival estimator and Cox proportional hazards regression. Hazard Ratios (HR) for the TAM/AI comparison, were adjusted for chemotherapy, trastuzumab, age at diagnosis, lymph node status, grade, clinical T stage, and ovarian ablation. Results We included 1158 patients: 326 pre-, 306 peri- and 526 postmenopausal. Of these, 229 received TAM and 929 AI. During follow-up, 239 RFS and 184 OS events were observed. In the TAM treated group, 56 RFS and 45 OS events were observed, in the AI treated group 183 RFS and 139 RFS events were observed respectively. No differences in RFS were observed comparing AI to TAM treated patients in the premenopausal (HR 1.33; 95% CI 0.71-2.49; P=0.378) and postmenopausal (HR 0.84, 95%CI 0.54-1.32; P=0.456) group. However, perimenopausal patients benefitted significantly from AI compared with TAM (HR 0.50; 95% CI 0.27-0.95). Results were similar for OS: no significant benefit from AI when compared to TAM in pre- (HR 1.41; 95% CI 0.62-3.19; P=0.408) and postmenopausal (HR 0.75; 95% CI 0.47-1.22; P=0.245) patients while perimenopausal patients derived significant benefit from AI treatment (HR 0.42; 95% CI 0.20-0.85; P=0.016). Conclusion In this population based cohort study we observed superiority for AI over TAM in the treatment of ER+/HER2+ perimenopausal patients. Data were suggestive in favor of AI when compared to TAM for postmenopausal patients while an indication of worse outcome with AI was seen in premenopausal patients, consistent with results of the SOFT/TEXT trial. Although we used age as a proxy for menopausal status, our results are consistent with previous RCTs. Population based data may therefore provide a reliable source of information when new RCTs might not be feasible anymore. Citation Format: Dackus GMHE, Jozwiak K, Sonke GS, Van der Wall E, Van Diest PJ, Hauptmann M, Siesling S, Linn SC. How population-based data complement trial data in the adjuvant endocrine treatment of ER+/HER2+ breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-16.

Abstract ES8-3: Endocrine management of premalignant lesions and DCIS

Abstract It has been recognized for many years that there exist pathological entities associated with an increased risk of invasive breast cancer. The most frequently encountered are atypical hyperplasia (AH), lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS), although other diagnoses have also been identified. Often these lesions are discovered incidentally, and when diagnosed are found to confer a wide range of elevated breast cancer risk. Clinical management of these conditions has largely consisted of surveillance, sometimes with the addition of endocrine therapy. The selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, have been the mainstay of endocrine therapy in this setting. A prospective randomized trial, NSABP P-1 randomized over 13,000 high risk women, defined by a Gail score >1.66, to either 5 years of tamoxifen or placebo.1 Tamoxifen reduced the risk of invasive breast cancer by 49% (p<.00001), with the greatest risk reduction seen in women with ADH or LCIS. The IBIS I study also compared to tamoxifen to placebo and confirmed a risk reduction with tamoxifen, although lower than that reported initially in the P-1 trial (hazard ratio [HR] 0.72 [95% CI 0.59-0.88], p=0.001).2 Most recently, the role of aromatase inhibitors as chemoprevention in this setting has been studied; the results of IBIS II trial, which randomized 3864 high risk postmenopausal women to anastrozole or placebo, found a substantial risk reduction in the AI group (hazard ratio 0.47, 95% CI 0.32-0.68, p<0.0001).3 Endocrine therapy in the adjuvant setting has been reported for DCIS in two prospective clinical studies, the NSABP-B24 and UK/ANZ trials. A meta-analysis of these two trials demonstrated that tamoxifen after lumpectomy for DCIS reduced recurrence of both ipsilateral (HR 0.75; 95% CI 0.61 to 0.92) and contralateral (RR 0.50; 95% CI 0.28 to 0.87) DCIS.4 There was a trend towards decreased ipsilateral invasive cancer (HR 0.79; 95% CI 0.62 to 1.01) and reduced contralateral invasive cancer (RR 0.57; 95% CI 0.39 to 0.83). In addition, the findings of NSABP B-35 randomizing postmenopausal women with ER-positive DCIS reported that 10-year point estimates for DFS were 77.9% for tamoxifen and 82.7% for anastrozole.5 Future challenges for this field will include more precise patient selection for these treatments, as all confer risk of side effects. These have resulted in poor uptake of chemoprevention despite the definitive benefit demonstrated in the large randomized studies. In addition, the utility of endocrine therapy as primary treatment for low risk DCIS or in the neoadjuvant setting are important questions which are currently under investigation. More precise quantification and communication of the risks and benefits of the endocrine therapies will be increasingly needed in order to maximize the benefits of endocrine intervention in this setting. 1Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-88, 1998 2Cuzick J, Sestak I, Cawthorn S, et al: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 16:67-75, 2015 3Cuzick J, Sestak I, Forbes JF, et al: Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383:1041-8, 2014 4Staley H, McCallum I, Bruce J: Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database Syst Rev 10:CD007847, 2012 5Margolese RG: Primary Results of NRG Oncology/NSABP B-35: A Clinical Trial of Anastrozole vs Tamoxifen in Postmenopausal Patients with DCIS. J Clin Oncol 33, 2015 (suppl; abstr LBA500), 2015. Citation Format: Hwang ES. Endocrine management of premalignant lesions and DCIS. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES8-3.

Personalized adjuvant therapies: Lessons from the past: The opening address by the St. Gallen 2013 award recipient

For several decades, personalized adjuvant therapies have been prescribed based on features that predict response to specific types of treatment. In this summary four specific issues regarding adjuvant therapies are described. Each one developed using information from past experience and is ready to be challenged by future findings from clinical trials and maturation of follow-up data. 1) Accuracy of determination of steroid hormone receptors and of HER2-status was the key feature in International Breast Cancer Study Group (IBCSG) and Breast International Group (BIG) trials. 2) Investigations on ovarian function suppression in IBCSG clinical trials led to the design of two trials (SOFT and TEXT), which are likely to lead to improved adjuvant therapy for premenopausal women with breast cancer. 3) Data from the BIG 1–98 trial of letrozole vs tamoxifen for postmenopausal patients with endocrine-responsive breast cancer provided information on which patients might obtain increased benefit from aromatase inhibitors and which might achieve similar treatment outcome with tamoxifen alone. 4) Finally, low-dose, frequently administered cytotoxics (metronomic chemotherapy) were tested in advanced disease with surprisingly favorable disease control and very low incidence of side effects. Personalized treatments are likely to improve substantially with increasingly accurate determination of their targets and by using risk- and toxicity-modulated therapies.

One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer

PurposeWe report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes. MethodsPostmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5cm were randomly assigned to 1year of tamoxifen, or cyclophosphamide 600mg/m2, methotrexate 40mg/m2 and fluorouracil 600mg/m2 intravenously on day 1 every 4weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed. ResultsFrom October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease-free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71–0.93; P=0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85–1.08; P=0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 ⩽14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (Pinteraction=0.45). ConclusionCMF added to 1year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.

Association of the phosphorylation of the estrogen receptor at serine 118 and 167 with prognosis in postmenopausal breast cancer patients.

562 Background: The sensitivity of the estrogen receptor (ERα) to anti-estrogen therapy can be affected by phosphorylation events. In premenopausal breast cancer patients, phosphorylation of the ERα at serine 118 (ERαS118-p) is predictive for benefit from adjuvant tamoxifen. Since ERαS118-p represents the common hallmark of different signaling cascades that differ in E2 dependency, the resulting effect on estrogen sensitivity may differ between pre- and postmenopausal patients. Phosphorylation of serine 167 (ERαS167-p) has been associated with favorable disease outcome, but whether ERαS167-p can predict tamoxifen sensitivity is currently unknown. We tested the predictive value of both ERαS118-p and ERαS167-p for benefit from adjuvant tamoxifen in postmenopausal breast cancer patients. Methods: We collected primary tumor blocks from 563 ERα positive (stage I-III) postmenopausal patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial). The median follow-up of patients without a recurrence event was 9.4 years. Immunohistochemistry was performed on a TMA using monoclonal antibodies for ERαS118-p and ERαS167-p. The percentage of positive nuclei was scored and a score of ≥ 10 % was considered as positive. Multivariate Cox models were used to assess hazard ratios (HRs) for recurrence free interval and the interaction between these phosphorylations and tamoxifen treatment. Results: We did not find a significant interaction between either ERαS118-p (p=0.99) or ERαS167-p (p=0.44) and tamoxifen, suggesting that the relative benefit from adjuvant tamoxifen in postmenopausal patients is not dependent on the presence of one of these phosphorylations. Both tamoxifen treated patients as well as control patients had a better prognosis when their tumor was positive for ERαS118-p (adjusted HR 0.60 p=0.02) or ERαS167-p (adjusted HR 0.62, p=0.02) compared to patients whose tumor did not express these ERα phosphorylations. Conclusions: In postmenopausal patients ERαS118-p and ERαS167-p are both associated with better prognosis, but do not predict differential benefit from tamoxifen.

Putting the Cardiovascular Safety of Aromatase Inhibitors in Patients with Early Breast Cancer into Perspective

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.

Abstract P4-08-01: ESR1 Gene Aberrations Correlate with ER Protein Levels Measured by DCC and IHC

Abstract Background: The Estrogen receptor alfa (ER) is an established biomarker that has been studied in details on the protein and RNA level. Recently, the existence of amplifications and deletions of the ESR1 gene have been documented (1-3), although the frequency of the aberrations has been extensively debated. Here we hypothesize that a positive correlation exists between ESR1 gene copy number and ER protein content measured by both a biochemical ligand assay, dextran coated charcoal (DCC), and immunohistochemistry (IHC). Material and Methods: From 289 primary high-risk breast cancer patients, randomized in the DBCG 77C trial between August 1977 and November 1982, ER data from DCC analyses was available. An ER positive tumor was defined as ≥10 fmol ER/mg protein (4). Archival tumor tissue was available from 257 patients. ESR1 copy number was analyzed with Dako Histology FISH Accessory Kit (K5599, DAKO, Glostrup, Denmark) using a probe covering the ESR1 gene at 6q25 and a centromere 6 reference probe (3). IHC analysis for ER was applied on archival paraffin embedded tissue using the antibody ER1D5 (DAKO), 1:200 with a positive cut off value of 10% ER positive tumor cells. Results: ESR1 FISH analysis was performed successfully in 215 (84%) patients. Amplification (ratio ESR1/CEN-6≥2) was observed in 47 of 215 patients (22%) and ESR1 deletion (ratio ESR1/CEN-6<0.8) was observed in 69 (32%). A positive correlation of ER-DCC with both FISH ESR1 and ER-IHC was found (P<0.0001). The ESR1 amplified tumors had higher average ER-DDC values compared to ESR1 normal tumors (ratio ESR1/ CEN6: 0,80-1,29) and tumors with ESR1 gain (ratio ESR1/CEN6: 1,30-1,99), while deleted tumors had lower ER-DCC values as illustrated in Figure 1. A significant difference p=0.005 was found for the ESR1 deleted tumors compared to the ESR1 amplified tumors. Fig. 1 Box plut showing the ER content according to ESR1/CEN-6 status Discussion: Amplification of the ESR1 gene is associated with higher ER protein content by ER-DCC and more intense immunoreactivity by IHC while ESR1 deletions are associated with decreased content and immunoreactivity compared to tumors with normal ESR1 gene copy numbers. Major variations in ER content and immunoreactivity are however observed within tumors with a normal ESR1 copy number, and other mechanisms than gene aberrations seem to contribute.

Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal patients with hormone receptor positive breast cancer

The estrogen receptor (ER) is the target of tamoxifen, but endocrine therapies do not benefit all patients with ER positive tumors. We therefore hypothesized that copy number changes in the ESR1 gene, encoding ER, confer resistance. Within a consecutive series of ER positive, postmenopausal patients allocated to 5 years tamoxifen, we identified 61 patients with recurrence less than 4 years and 48 patients without recurrence at least 7 years after initiation of adjuvant tamoxifen. Archival tissue containing primary tumor was collected from 97 patients (89%). Tumor samples were analyzed for ESR1 copy number changes using FISH with a probe covering the ESR1 gene at 6q25 and a reference probe covering the centromere of chromosome 6. The assay was validated in a material of 120 normal breast samples. FISH analysis for ESR1 was successful in 91 patients (94%). Amplification (ratio ESR1/CEN-6 ≥ 2.0) was observed in 11 of 50 (22%) patients with early recurrence, compared to two of 41 (5%) patients without recurrence. The difference is statistically significant (P = 0.033). In both groups, two patients with ESR1 deletion (ratio ESR1/CEN-6 < 0.8) were identified. ESR1 amplification was significantly associated with poor disease-free survival (P = 0.0054) and overall survival (P = 0.0004). This pilot study supports our hypothesis that ESR1 amplification is associated with a poorer outcome following adjuvant treatment with tamoxifen in ER positive early breast cancer. This study also revealed the existence of ESR1 deletions. The prognostic and predictive impact of ESR1 copy number changes needs further exploration in clinical trials.

Combining and Sequencing Adjuvant Chemotherapy and Tamoxifen in Postmenopausal Women with Node-Positive Breast Cancer

Evaluation of: Albain KS, Barlow WE, Ravdin PM et al.; Breast Cancer Intergroup of North America: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a Phase 3, open-label, randomised controlled trial. Lancet 374(9707), 2055–2063 (2009). This Phase III trial randomized 1477 postmenopausal women with hormone receptor-positive, node-positive operable breast cancer to receive 5 years of adjuvant tamoxifen alone, or tamoxifen given concurrently or after cyclophosphamide, doxorubicin and fluorouracil (CAF) chemotherapy. After 13 years of follow-up, the 10-year disease-free survival was significantly improved in the group receiving the combination of CAF chemotherapy and tamoxifen, compared with the tamoxifen-alone group (57 vs 48%, respectively; p = 0.002); overall survival was also marginally improved in the combination group (65 vs 60%; p = 0.0057). Sequential tamoxifen given after CAF chemotherapy marginally improved disease-free survival compared with concurrent tamoxifen and chemotherapy (60 vs 53%, respectively; p = 0.057). Chemotherapy with CAF together with sequential tamoxifen is a more effective adjuvant therapy for postmenopausal women with hormone receptor-positive, node-positive breast cancer compared with tamoxifen alone.

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Concurrent or Sequential Adjuvant Hormonoradiotherapy after Conservative Surgery for Early-Stage Breast Cancer: Clinical Results of the CO-HO-RT Phase II Randomized Trial.

Abstract Purpose: Letrozole (LET) has recently been shown to be superior to tamoxifen for postmenopausal patients (pts). In addition, LET radiosensitizes breast cancer cells in vitro. We conducted a phase II randomized study to evaluate concurrent and sequential radiotherapy (RT)-LET in the adjuvant setting. We present here clinical results with a minimum follow-up of 24 months.Patients and Methods: Postmenopausal pts with early-stage breast cancer were randomized after conservative surgery to either: A) concurrent RT-LET (LET started 3 weeks before the first day of RT) or B) sequential RT-LET (LET started 3 weeks after the end of RT). Whole breast RT was delivered to a total dose of 50 Gy. A 10-16 Gy boost was allowed according to age and pathological prognostic factors. Pts were stratified by center, adjuvant chemotherapy, boost, and radiation-induced CD8 apoptosis (RILA). RILA was performed before RT as previously published (Ozsahin et al. Clin Cancer Res, 2005). An independent monitoring committee reviewed individual safety data. Skin toxicities were evaluated by two different clinicians at each medical visit (CTCAE v3.0). Lung CT-scan and functional pulmonary tests were performed regularly. DNA samples were screened for SNPs in candidate genes as recently published (Azria et al., Clin Cancer Res, 2008).Results: A total of 150 pts were randomized between 01/05 and 02/07. Median follow-up is 26 months (range, 3-40 months). No statistical differences were identified between the two arms in terms of mean age; initial TNM; median surgical bed volume; post surgical breast volume. Chemotherapy and RT boost were delivered in 19% and 38% of pts, respectively. Nodes received 50 Gy in 23% of patients without differences between both arms. During RT and within the first 6 weeks after RT, 10 patients (6.7%) presented grade 3 acute skin dermatitis during RT but no differences were observed between both arms (4 and 6 patients in arm A and B, respectively). At 26 month of follow-up, grade 2 and more radiation-induced subcutaneous fibrosis (RISCF) was present in 4 patients (3%) without any difference between arm A (n = 2) and B (n = 2), p=0.93. In both arms, all patients that presented a RICSF had a RILA lower than 16%. Sensitivity and specificity were 100% and 39%, respectively.No acute lung toxicities were observed and quality of life was good to excellent for all patients.SNPs analyses are still on-going (Pr Rosenstein, NY).Conclusion: Acute and early late grade ≥ 2 dermatitis were similar in both arms. The only factor that influenced RISCF was a low radiation-induced lymphocyte apoptosis yield. We confirmed prospectively the capacity of RILA for identifying hypersensitive patients to radiation. Indeed, patients with RILA superior to 16% did not present late effects to radiation and confirmed the first prospective trial we published in 2005 (Ozsahin et al., Clin Cancer Res). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 956.

Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8.94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0.76, 95% CI 0.64-0.91; p=0.002) but only marginally for the secondary endpoint of overall survival (HR 0.83, 0.68-1.01; p=0.057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0.84, 0.70-1.01; p=0.061) or overall survival (HR 0.90, 0.73-1.10; p=0.30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. National Cancer Institute (US National Institutes of Health).

Endocrine Effects of Adjuvant Letrozole Compared With Tamoxifen in Hormone-Responsive Postmenopausal Patients With Early Breast Cancer: The HOBOE Trial

PURPOSE We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone-responsive early breast cancer within an ongoing phase III trial. PATIENTS AND METHODS Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. CONCLUSION Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer

Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)

Endocrine effects of adjuvant letrozole versus tamoxifen in hormone responsive postmenopausal early breast cancer patients: results from the HOBOE randomized trial.

Abstract Abstract #1150 Purpose. We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone responsive early breast cancer, within an ongoing phase 3 trial (HOrmonal adjuvant treatment BOne Effects – HOBOE, ClinicalTrial.gov id: NCT00412022).&amp;#x2028; Patients and Methods. Patients were randomised to receive tamoxifen or letrozole ± zoledronate. Serum values of 17-b-estradiol, FSH, LH, testosterone, dehydroepiandrosterone-solphate, progesterone, and cortisol were measured at baseline, after 6 and 12 months of treatment. For each hormone, baseline, 6 and 12-month values were compared between treatment groups, by the exact Wilcoxon-Mann-Whitney test.&amp;#x2028; Results. At December 31, 2006, 157 postmenopausal patients had been enrolled into the study; baseline data were available for 139 patients (88.5%), 43 assigned to tamoxifen and 96 assigned to letrozole. Median age was 61 and 62 years in the two groups, respectively. Baseline values were similar between the two groups for all hormones. At 6 and 12 months, levels of 17-b-estradiol were significantly lower with letrozole as compared with tamoxifen (p=0.0003 and p&amp;lt;0.0001, respectively). Patients treated with letrozole also showed higher levels of progesterone and testosterone at 6 (p=0.001 and p=0.01, respectively) and 12 months (p=0.004 and p=0.02, respectively) than those treated with tamoxifen. FSH and LH were lower (all p&amp;lt;0.0001 for both hormones), while cortisol was higher (p=0.003 at 6 and 0.001 at 12 months) with tamoxifen than with letrozole.&amp;#x2028; Conclusion. To our knowledge, this is the first study reporting on endocrine effects of letrozole as adjuvant treatment of postmenopausal early breast cancer and allowing a prospective comparison with tamoxifen. Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared to tamoxifen. Long-term impact needs to be studied. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1150.

Co-expression of estrogen receptor α and Apolipoprotein D in node positive operable breast cancer – possible relevance for survival and effects of adjuvant tamoxifen in postmenopausal patients

Background. Estrogen receptor-α (ERα) is an important prognostic and predictive marker in breast cancer. ERα signaling normally down-regulates expression of Apolipoprotein D (ApoD), a lipocalin that binds, transports or chelates lipophilic ligands, including tamoxifen (TAM). Hence, the co-expression of ApoD may therefore identify clinical relevant subgroups of ERα positive breast cancer patients. Material and methods. ApoD, ERα, and progesterone receptor (PR) protein expressions were determined by immunohistochemistry (IHC) in primary tumors of 290 patients with operable breast cancer. The median follow-up was 12 years. Patients were stratified according to age, nodal stage and the expression of ERα and the combined cytoplasm and nuclear staining of ApoD (ApoDCN). Results. In elderly women (≥70 years) (n = 76), ApoDCN expression identified different prognostic subgroups in ERα positive patients (Trend: p < 0.0001). Multivariate analysis in this age group (n = 72), showed that the ERα-positive /ApoDCN-negative subgroup had a better breast cancer specific survival (BCSS) compared with the ERα-positive/ApoDCN-positive group (hazard ratio (HR) = 4.3; 95% CI = 1.6–11.9; p = 0.005). This difference was predominantly seen in the node positive patients (n = 30) (HR = 10.5; 95% CI = 2.3–47.6; p = 0.002). In a subset of postmenopausal ERα-positive/node positive patients (n = 60) previously enrolled in a trial on 2 year adjuvant TAM 20 mg vs. placebo, a better BCSS was observed in ApoDCN negative patients compared to placebo (p = 0.02). In ApoDCN positive patients, adjuvant TAM did not provide any survival benefit. Discussion. ERα and ApoDCN co-expression seems to be of prognostic importance in node positive elderly patients with operable breast cancer. In addition, we hypothesize that ApoDCN expression may be a novel marker and/or mechanism of TAM resistance in postmenopausal node positive patients. Thus, when targeting the ERα pathway in these patients, the ApoD status of the tumor may be of clinical relevance.

Locally advanced breast cancer

The management of locally advanced breast cancer (LABC) is guided by scientific advances but is limited by local resources and expertise. LABC remains very common in low-resource countries. The Systemic Therapy Focus Group met as part of the Breast Health Global Initiative (BHGI) Summit in Budapest, Hungary, in October 2007 to discuss management and implementation of primary systemic therapy (PST) for LABC. PST is standard treatment for large operable breast cancer in enhanced-resource settings and, in all resource settings, should be standard treatment for inoperable breast cancer and for LABC. Standard PST includes anthracycline-based chemotherapy. The addition of sequential taxanes after anthracycline improves pathologic responses and breast-conservation rates and is appropriate at enhanced-resource levels; however, costs and lack of clear survival benefit do not justify their use at limited-resource levels. It remains to define better the role of endocrine therapy as PST, but it is acceptable in elderly women. Aromatase inhibitors have produced better results than tamoxifen in postmenopausal patients and are used in enhanced-resource settings. The less expensive tamoxifen remains useful in low-resource countries. Trastuzumab combined with chemotherapy yields high pathologic response rates in patients with HER2/neu-overexpressing tumors; its use in low-resource countries is limited by high costs. Most studies on PST of LABC were conducted in countries with enhanced resources. BHGI encourages conducting clinical trials in countries with limited resources.

Aromatase Inhibitors: A New Reality for the Adjuvant Endocrine Treatment of Early-Stage Breast Cancer in Postmenopausal Women

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the "gold standard" adjuvant treatment for patients with hormone-receptor-positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. In the last few years, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. The goal of this article was to review the results of recent randomized trials comparing AIs to tamoxifen in postmenopausal women in the adjuvant setting. Two strategies have been utilized: a direct upfront comparison in which both tamoxifen and AIs were given for 5 years or an early switch in which AIs were administered after 2-3 years of tamoxifen for 3-2 years or vice versa. Both strategies have shown a superiority of AIs over tamoxifen and a different safety profile but, the optimal treatment modality has yet to be defined. Moreover, in an attempt to further reduce patients' risk of recurrence after the administration of tamoxifen for 5 years, three trials have evaluated the role of prolonging the adjuvant treatment with AIs for 5 more years in comparison to placebo (late switch). A significant improvement of disease-free survival and of overall survival in the subgroup of node-positive patients, at least in one trial, has been observed with AIs. Despite these important results several unanswered questions remain and the results of ongoing trials will hopefully clarify some of them.