Premenopausal Early-stage Breast Cancer Research Articles

Abstract PS5-38: Short course of preoperative tamoxifen in premenopausal breast cancer patients: Biomarker changes and survival

Abstract Background: Luminal HER2 negative breast cancer is a highly heterogeneous disease, which complicates the choice of optimal systemic treatment in early stage disease. It is known that in postmenopausal patients (pts) Ki67 level after short course of preoperative endocrine therapy (PET) correlates with survival in contrast to baseline level. We performed the trial of PET in premenopausal early stage breast cancer pts.Patients and methods: This is a non-randomized, open-label, single-arm, phase II study of short course of preoperative tamoxifen in premenopausal pts. Primary objective was a decline in Ki67 level below 10%, secondary objectives were biomarker changes and disease free survival. Between 2011 and 2017 74 pts with T1-2N0-1M0 ER+ HER2 negative breast cancer were included in the study, median age was 45 (range, 32-55), median baseline Ki67 30% (range, 5-96), median stromal TILs 5% (range, 0-40). All pts were treated with tamoxifen for 2-3 weeks before surgery. Median follow-up was 56 months (range, 29.6-124.3).Results: There was a statistically significant decline in Ki67 during the short course of endocrine therapy (p<0,001), median Ki67 level after PET was 20% (range 3-75). Also we noticed significant decline in estrogen receptor (ER) expression level (p=0,001), but not in progesterone receptor (PR) expression. There was an increase in the level of stromal TILs (p=0.09). Baseline level of Ki67 and tumor grade had significant impact on decline in Ki67 below 10%. None of 28 pts with baseline Ki67>30% had post-PET Ki67<10% in comparison with 20,5% (9/44) with baseline Ki67 10-30%. No pts with baseline TILs≥20% had decline in Ki67 below 10%. Baseline level of Ki67 did not correlate with survival, 3-year DFS with baseline Ki67≤30 was 94,4%, Ki67>30% - 92,6% (p=0.54). Also there was no difference in survival according to Ki67 level after the course of endocrine therapy: with post-PET Ki67<10% 3-year DFS was 100% (none of pts was treated with chemotherapy), 10-30 – 92,4%, >30 – 94,4% (p=0.61). We explain this with the changes in adjuvant treatment in pts with high (>30%) level of Ki67 after endocrine therapy – all pts were receiving adjuvant chemotherapy and, what is more important, they also had ovarian suppression and tamoxifen has been changed to aromatase inhibitors (AI). Conclusion: to our knowledge this is the first study of the short course of PET in premenopausal pts. We demonstrated that post-PET Ki67 level can be used for individualization of adjuvant therapy (intensification with chemotherapy, ovarian suppression, AI in poor responders and avoiding of chemotherapy in good responders). Further prospective randomized trials are warranted. Citation Format: Mona Frolova, Marina Stenina, Alexander Petrovsky, Olga Krohina, Sergei Tjulandin. Short course of preoperative tamoxifen in premenopausal breast cancer patients: Biomarker changes and survival [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-38.

Low Z-4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen.

Low steady-state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor-positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z-endoxifen and Z-4-hydroxy-tamoxifen (Z-4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n=191) we confirmed an inferior BC -specific survival in patients with the previously described serum concentration threshold of Z-4OHtam≤3.26nm (HR=2.37, 95% CI=1.02-5.48, P=0.039). The 'dose-response' survival trend in patients categorized to ordinal concentration cut-points of Z-4OHtamoxifen (≤3.26, 3.27-8.13, >8.13nm) was also replicated (P-trend log-rank=0.048). Z-endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5-year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.

Inhibition of RANK signaling in breast cancer induces an anti-tumor immune response orchestrated by CD8+ T cells

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8+ T cells, and reduces macrophage and neutrophil infiltration. CD8+ T cells mediate the attenuated tumor phenotype observed upon RANK loss, whereas neutrophils, supported by RANK-expressing tumor cells, induce immunosuppression. RANKL inhibition increases the anti-tumor effect of immunotherapies in breast cancer through a tumor cell mediated effect. Comparably, pre-operative single-agent denosumab in premenopausal early-stage breast cancer patients from the Phase-II D-BEYOND clinical trial (NCT01864798) is well tolerated, inhibits RANK pathway and increases tumor infiltrating lymphocytes and CD8+ T cells. Higher RANK signaling activation in tumors and serum RANKL levels at baseline predict these immune-modulatory effects. No changes in tumor cell proliferation (primary endpoint) or other secondary endpoints are observed. Overall, our preclinical and clinical findings reveal that tumor cells exploit RANK pathway as a mechanism to evade immune surveillance and support the use of RANK pathway inhibitors to prime luminal breast cancer for immunotherapy.

Switching to anastrozole plus goserelin vs continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: preliminary results from a randomized trial.

PurposeTo assess the efficacy, safety, and quality-of-life impact of switching adjuvant treatment in hormone receptor-positive primary breast cancer patients who are still premenopausal after 2–3 years of tamoxifen therapy to anastrozole plus goserelin as compared with continuing tamoxifen over a total period of 5 years.Patients and methodsHormone receptor-positive, premenopausal, lymph node-positive, or tumor size ≥4 cm breast cancer patients who had received tamoxifen for 2–3 years were randomly assigned to continue tamoxifen treatment (TAM group) or switch to adjuvant anastrozole plus goserelin (ADD group) and continue treatment for another 2–3 years (total treatment duration 5 years). Endpoints evaluated were adverse events (AEs), changes in bone mineral density, quality of life, and disease-free survival-related events.ResultsA total of 62 patients (33 in the ADD group and 29 in the TAM group) were evaluated. Grade 3–4 drug-related AEs occurred in five patients (15.2%) in the ADD group vs none in the TAM group. In the ADD group, arthralgias were the most common AEs (5/33 patients; 15.2%), and three patients in this group were discontinued because of AEs. Treatment was temporarily suspended due to AEs in three patients (9.1%) in the ADD group and one patient (3.4%) in the TAM group. Compared with continuing TAM therapy, switching to anastrozole plus goserelin did not result in any worsening of bone mineral density or quality of life. During a median follow-up of 34 months, five patients (15.2%) in the ADD group had disease-free survival events vs four patients (13.8%) in the TAM group.ConclusionFor early-stage breast cancer patients who remain premenopausal following 2–3 years of adjuvant tamoxifen therapy, switching to anastrozole plus goserelin therapy was safe with tolerable adverse effects. However, it did not show superior efficacy compared to remaining on tamoxifen treatment.Trial RegistrationClinicalTrials.gov (identifier NCT01352091).

Prediction of Postmenopausal Status in Premenopausal Early Stage Breast Cancer Patients after Adjuvant Chemotherapy

Prediction of Postmenopausal Status in Premenopausal Early Stage Breast Cancer Patients after Adjuvant Chemotherapy

An evaluation study of the determinants of future perspective and global Quality of Life in Spanish long-term premenopausal early-stage breast cancer survivors.

Aim of the studyQuality of life (QL) is important in premenopausal long-term breast cancer survivors. In this study we assessed QL and factors associated with future perspective and global QL in premenopausal early-stage long-term breast cancer survivors from Spain.Material and methods243 premenopausal stage I-IIIA relapse-free breast cancer patients who had received surgery 5–20 years previously completed EORTC QLQ-C30 and QLQ-BR23 questionnaires once during follow-up. Univariate and multivariate logistic regression analyses were performed.ResultsQL mean scores were high in most areas (> 80 in functioning; < 20 in symptoms). The main factors for future perspective were emotional and social functioning, fatigue, breast symptom, and body image. The main factors for global QL were fatigue, pain and physical functioning, and emotional and social functioning. The best logistic model to explain future perspective associated high emotional and social functioning and low breast symptoms with a lower risk of low future perspective (R2 = 0.56). Higher scores in physical and emotional functioning and lower scores in fatigue were associated with a lower risk of low global QL (R2 = 0.50).ConclusionsPsychological, social, and physical factors were found to be possible determinants of global QL and future perspective. QL in premenopausal early-stage long-term breast cancer survivors may benefit from multidisciplinary treatment.

1948 Switching to anastrozole plus goserelin versus continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: Preliminary results from a randomized trial

1948 Switching to anastrozole plus goserelin versus continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: Preliminary results from a randomized trial

The prognostic value of IL10 and TNF alpha functional polymorphisms in premenopausal early-stage breast cancer patients.

BackgroundInterleukin-10 and tumor necrosis factor α play an important role in breast carcinogenesis. Genes, encoding those two cytokines, contain single nucleotide polymorphisms, which are associated with differential levels of gene transcription. This study analyzes single nucleotide polymorphisms in interleukin 10 and tumor necrosis factor α genes and their contribution to breast cancer phenotype, lymph node status and survival in a group of young Lithuanian women with early-stage breast cancer patients.ResultsWe genotyped 100 premenopausal Eastern European (Lithuanian) patients with stage I-II breast cancer, ≤50 years old at the time of diagnosis, for interleukin 10 -592A > C, −819C > T and -1082A > G and tumor necrosis factor α -308G > A single nucleotide polymorphisms in the gene promoter region. We used the polymerase chain reaction, namely a restriction fragment length polymorphism method, for a SNP analysis. All genotypes were in Hardy-Weinberg equilibrium and had the same distribution as the HapMap CEU population. Holders of IL10 -592A > C heterozygous IL10 -592 AC genotype had a higher probability of estrogen receptor positive breast cancer phenotype than homozygous variants (P = 0.017). Phased ACC haplotype of IL10 polymorphisms was associated with younger age of diagnosis (P = 0.017). Of all the tested single nucleotide polymorphisms, only TNFα -308G > A has revealed a prognostic capability for breast cancer survival. GA genotype carriers, compared to GG, showed a significant disadvantage in progression-free survival (P = 0.005, adjusted hazard ratio (HR) = 4.631, 95 % confidence interval (CI) = 1.587 – 13.512), metastasis-free survival (P = 0.010, HR = 4.708, 95 % CI = 1.445 – 15.345) and overall survival (P = 0.037, HR = 4.829, 95 % CI = 1.098 – 21.243).ConclusionsAccording to our data, IL10 -1082A > G, −819 T > C, −592A > C polymorphisms and phased haplotypes have not revealed a prognostic value for breast cancer. On the contrary, the TNFα -308 polymorphism might modulate the risk and contribute to the identification of patients at a higher risk of breast cancer recurrence, metastasis and worse overall survival among young Lithuanian early-stage breast cancer patients.

What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis

To evaluate the incidence of chemotherapy-induced amenorrhea (CIA) and its therapeutic impact in premenopausal breast cancer patients. A systematic search was performed to identify clinical studies that compared the incidence of CIA with different chemotherapy regimens and oncological outcomes with and without CIA. The fixed-effects and random-effects models were used to assess the pooled estimates. Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. A total of 15,916 premenopausal breast cancer patients from 46 studies were included. The cyclophosphamide-based regimens, taxane-based regimens, and anthracycline/epirubicin-based regimens all increased the incidence of CIA with pooled odds ratios of 2.25 (95 % CI 1.26-4.03, P = 0.006), 1.26 (95 % CI 1.11-1.43, P = 0.0003) and 1.39 (95 % CI 1.15-1.70, P = 0.0008), respectively. The three-drug combination regimens of cyclophosphamide,anthracycline/epirubicin, and taxanes (CAT/CET) caused the highest rate of CIA compared with the other three drug combinations (OR 1.41, 95 % CI 1.16-1.73, P = 0.0008). Tamoxifen therapy was also correlated with a higher incidence of CIA, with an OR of 1.48. Patients with CIA were found to exhibit better disease-free survival (DFS) and overall survival (OS) compared with patients without CIA. With respect to molecular subtype, this DFS advantage remained significant in hormone-sensitive patients (HR 0.61, 95 % CI 0.52-0.72, P < 0.00001). The current meta-analysis has demonstrated that anthracycline/epirubicin, taxanes, cyclophosphamide, and tamoxifen all contributed to elevated rates of CIA, and CIA was not merely a side effect of chemotherapy but was a better prognostic marker, particularly for ER-positive premenopausal early-stage breast cancer patients. However, this topic merits further randomized control studies to detect the associations between CIA and patient prognosis after adjusting for age, ER status, and other influential factors.

Racial Disparities in Cancer Survival Among Randomized Clinical Trials Patients of the Southwest Oncology Group

Racial disparities in cancer outcomes have been observed in several malignancies. However, it is unclear if survival differences persist after adjusting for clinical, demographic, and treatment variables. Our objective was to determine whether racial disparities in survival exist among patients enrolled in consecutive trials conducted by the Southwest Oncology Group (SWOG). We identified 19 457 adult cancer patients (6676 with breast, 2699 with lung, 1244 with colon, 1429 with ovarian, and 1843 with prostate cancers; 1291 with lymphoma; 2067 with leukemia; and 2208 with multiple myeloma) who were treated on 35 SWOG randomized phase III clinical trials from October 1, 1974, through November 29, 2001. Patients were grouped according to studies of diseases with similar histology and stage. Cox regression was used to evaluate the association between race and overall survival within each disease site grouping, controlling for available prognostic factors plus education and income, which are surrogates for socioeconomic status. Median and ten-year overall survival estimates were derived by the Kaplan-Meier method. All statistical tests were two-sided. Of 19 457 patients registered, 2308 (11.9%, range = 3.9%-21.6%) were African American. After adjustment for prognostic factors, African American race was associated with increased mortality in patients with early-stage premenopausal breast cancer (hazard ratio [HR] for death = 1.41, 95% confidence interval [CI] = 1.10 to 1.82; P = .007), early-stage postmenopausal breast cancer (HR for death = 1.49, 95% CI = 1.28 to 1.73; P < .001), advanced-stage ovarian cancer (HR for death = 1.61, 95% CI = 1.18 to 2.18; P = .002), and advanced-stage prostate cancer (HR for death = 1.21, 95% CI = 1.08 to 1.37; P = .001). No statistically significant association between race and survival for lung cancer, colon cancer, lymphoma, leukemia, or myeloma was observed. Additional adjustments for socioeconomic status did not substantially change these observations. Ten-year (and median) overall survival rates for African American vs all other patients were 68% (not reached) vs 77% (not reached), respectively, for early-stage, premenopausal breast cancer; 52% (10.2 years) vs 62% (13.5 years) for early-stage, postmenopausal breast cancer; 13% (1.3 years) vs 17% (2.3 years) for advanced ovarian cancer; and 6% (2.2 years) vs 9% (2.7 years) for advanced prostate cancer. African American patients with sex-specific cancers had worse survival than white patients, despite enrollment on phase III SWOG trials with uniform stage, treatment, and follow-up.

Predictors of permanent menopause after chemotherapy for early-stage breast cancer in premenopausal women

575 Background: Optimal choice of endocrine therapy for early-stage breast cancer differs with menopausal status. While amenorrhea is common during adjuvant chemotherapy, there is currently no available test to establish when menopause is permanent. The aim of this study was to determine the age cutoff after which resumption of menses is unlikely following chemotherapy and to assess what additional risk factors may predict for persistent menopause at 5 years after initiation of chemotherapy. Methods: One hundred patients treated with chemotherapy for early-stage premenopausal breast cancer and who remained alive and free of recurrence at least 5 years from the start of treatment were enrolled. Participants were evaluated for current menstrual status and for baseline potential risk factors for menopause: age at start of chemotherapy, race, BMI, smoking history, age at menarche, irregular menses prior to chemotherapy, presence of menses during chemotherapy, type of chemotherapy regimen, hormonal therapy, ovarian protection during chemotherapy, and number of doses of alkylating agent (cyclophosphamide). Recursive partitioning analysis (RPA) was used to identify the age cutoff that best predicts permanent menopause; additional risk factors were assessed using logistic regression analysis. Results: Median age at start of chemotherapy was 43 (range 26–49). RPA identified age &gt;42 at the start of chemotherapy as a significant predictor of permanent menopause (p &lt; 0.001). Cessation of menses during chemotherapy was also associated with permanent menopause (p &lt; 0.001). Both variables remained significant in multivariate analysis (p &lt; 0.001), with the combination of these factors being associated with a 95.4% chance of permanent menopause. Conclusions: In this series, fewer than 5% of premenopausal patients who were at least 42 years old and who experienced cessation of menses during chemotherapy experienced any return of menses over at least 5 years. Upfront use of aromatase inhibitors as adjuvant endocrine therapy for premenopausal hormone-receptor positive breast cancer warrants further investigation for those who are at least 42 years of age and who experience amenorrhea with chemotherapy. No significant financial relationships to disclose.

What is the current status of ovarian suppression/ablation in women with premenopausal early-stage breast cancer?

The role of ovarian suppression/ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer has been evolving for more than a century. It is clear that OS/OA is an effective adjuvant therapy for these women, but despite numerous studies enrolling thousands of women, many unanswered questions remain. In particular, a major question is whether additional benefit is gained with combination treatment comprising luteinizing hormone-releasing hormone (LH-RH) agonists and tamoxifen over tamoxifen alone. Ongoing trials also are assessing the coupling of aromatase inhibitors (traditionally contraindicated in these patients because of paradoxic stimulation of estrogen production) and LH-RH agonists. Any potential disease-free or overall survival advantage of combination treatment must be balanced against a possible increase in adverse effects and impairment of quality of life. This review focuses on new data on how to incorporate OS/OA into the rational treatment of this challenging patient population.

What is the current status of ovarian suppression/ablation in women with premenopausal early-stage breast cancer?

The role of ovarian suppression/ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer has been evolving for more than a century. It is clear that OS/OA is an effective adjuvant therapy for these women, but despite numerous studies enrolling thousands of women, many unanswered questions remain. In particular, a major question is whether additional benefit is gained with combination treatment comprising luteinizing hormone-releasing hormone (LH-RH) agonists and tamoxifen over tamoxifen alone. Ongoing trials also are assessing the coupling of aromatase inhibitors (traditionally contraindicated in these patients because of paradoxic stimulation of estrogen production) and LH-RH agonists. Any potential disease-free or overall survival advantage of combination treatment must be balanced against a possible increase in adverse effects and impairment of quality of life. This review focuses on new data on how to incorporate OS/OA into the rational treatment of this challenging patient population.

Gene expression profiling and breast cancer care: What are the potential benefits and policy implications?

PurposeGene expression profiling has been proposed as an alternative to clinical guidelines to identify high-risk patients for adjuvant chemotherapy. However, the outcomes associated with gene expression profiling are not clear, and guidelines for the appropriate use of genomic technologies have not been established. MethodsWe developed a decision analytic model to evaluate the incremental cost and quality-adjusted life years of gene expression profiling versus NIH clinical guidelines in a hypothetical cohort of premenopausal early stage breast cancer patients 44 years of age. We conducted empirical analyses and identified literature-based data to inform the model, and performed probabilistic sensitivity analyses to evaluate uncertainty in the results. We interpreted the implications of our findings for treatment guidelines and policies. ResultsUse of gene expression profiling resulted in an absolute 5% decrease in the proportion of cases of distant recurrence prevented, 0.21 fewer quality-adjusted life years, and a cost savings of $2882. The chosen test cutoff value to identify a tumor as poor prognosis and the cost of adjuvant chemotherapy were the most influential parameters in the analysis, but our findings did not change substantially in sensitivity analyses. Regardless of the test cutoff used to identify a poor prognosis tumor, the gene expression profiling assay studied in our analysis, at its current level of performance, did not attain the threshold sensitivity (95%) necessary to produce equal or greater quality-adjusted life years than NIH guidelines. ConclusionAlthough the use of gene expression profiling in breast cancer care holds great promise, our analysis suggests additional refinement and validation are needed before use in clinical practice.

Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients.

The RPS6KB1 gene is amplified and overexpressed in approximately 10% of breast carcinomas and has been found associated with poor prognosis. We studied the prognostic significance of P70 S6 kinase protein (PS6K) overexpression in a series of 452 node-negative premenopausal early-stage breast cancer patients (median follow-up: 10.8 years). Immunohistochemistry was used to assess PS6K expression in the primary tumour, which had previously been analysed for a panel of established prognostic factors in breast cancer. In a univariate analysis, PS6K overexpression was associated with worse distant disease-free survival as well as impaired locoregional control (HR 1.80, P 0.025 and HR 2.50, P 0.006, respectively). In a multivariate analysis including other prognostic factors, PS6K overexpression remained an independent predictor for poor locoregional control (RR 2.67, P 0.003). To our knowledge, P70 S6 kinase protein is the first oncogenic marker that has prognostic impact on locoregional control and therefore may have clinical implications in determining the local treatment strategy in early-stage breast cancer patients.

Ovarian ablation for premenopausal early-stage breast cancer: an update.

Ovarian ablation is the oldest form of systemic treatment of breast cancer and consists of removal of the main source of estrogen biosynthesis in premenopausal women: Over the last century several different means of stopping ovarian function have been studied: surgical oophorectomy, ovarian irradiation, and more recently, chemical castration by gonadotropin-releasing hormone analog therapy. In unselected patients the response rate to ovarian ablation is of about 35% but the likelihood of response is considerably higher for patients with hormonal receptor-positive tumors, the therapy being most effective in women who are actively menstruating. In spite of this evidence, the role of ovarian ablation in the management of early-stage breast cancer still remains controversial. Here we review current evidence supporting the value of this ablative procedure as an adjuvant and update ongoing clinical research to refine our knowledge about its use.

The risk of premature menopause induced by chemotherapy for early breast cancer.

The objectives of this retrospective case series were to determine the prevalence and timing of menstrual abnormalities in early-stage breast cancer patients undergoing adjuvant methotrexate or anthracycline-based chemotherapy and to more fully assess the possible mechanism of the amenorrhea reported after chemotherapy. One hundred forty-two premenopausal patients undergoing adjuvant chemotherapy were analyzed for patient age, breast cancer stage, type of chemotherapy, and menstrual abnormalities before, during, and after chemotherapy completion. A 24-month minimum follow-up after chemotherapy completion was available for all patients. One hundred nine of 142 patients were evaluable. Sixty-nine patients (46 node negative, 23 node positive) received methotrexate-based chemotherapy, 33 patients (3 node negative, 30 node positive) received anthracycline-based chemotherapy, and 7 patients received both treatments (all node positive). Amenorrhea occurred in about a third of patients during chemotherapy (methotrexate groups 31%, anthracycline group 33%), and a higher proportion were amenorrheic 1 year after chemotherapy was completed (methotrexate group 45%, anthracycline group 46%). Abnormalities were more likely to occur in older premenopausal patients (Chi square = 6.18, p < 0.05), although 28% of patients under age 35 developed persistent abnormal menses. In some amenorrheic patients, follicle-stimulating hormone (FSH) levels were decreased within 6 months of chemotherapy (24.4 IU). The levels tended to be higher after chemotherapy (59.1 IU), suggesting ovarian failure. Menstrual abnormalities and menopause will frequently occur in premenopausal early-stage breast cancer patients, with 30% of all patients amenorrheic 1 year after chemotherapy.

The efficacy and cost-effectiveness of adjuvant therapy of early breast cancer in premenopausal women.

We used decision analysis to model the natural history of breast cancer in hypothetical cohorts of 45-year-old women receiving tamoxifen, chemotherapy, or combined therapy. We used recurrence and efficacy data from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), utility values from focus groups, and costs from clinic charges and Medicare data. Tamoxifen alone provides minimal benefit in estrogen receptor-negative (ER-; 0.2 to 0.4 months) and modest benefit in receptor-positive (ER+; 3.5 to 5.2 months) cancer. Chemotherapy adds substantial benefit independent of receptor status (4.9 to 10.7 quality-adjusted months). In ER+ cancer, combined therapy adds an additional benefit (1.2 to 2.1 months) compared with chemotherapy alone. The incremental costs (United States dollars) necessary to add an additional year of life to the average woman ranged from $4,300 to $11,400 for tamoxifen alone for ER+ cancer, $4,900 to $11,400 for chemotherapy alone, and $14,800 to $33,100 for combined therapy. In premenopausal early-stage breast cancer, chemotherapy adds substantial clinical benefit at a modest cost. Tamoxifen alone adds meaningful benefit only in ER+ cancer. Combined therapy is effective for all women, but is most beneficial and only cost-effective in ER+ women. If secondary effects of tamoxifen in reduction of cardiovascular and osteoporosis mortality are confirmed, then combined treatment may be optimal for all premenopausal women.