Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer

Background:

The objective of this study was to determine the optimal scheduling of 2.5 mg daily letrozole in neoadjuvant breast cancer patients to obtain pathological complete response (pathCR) and assess Ki-67 expression as an early predictor of response.

Patients and methods:

This single institution study comprised 120 oestrogen receptor (ER)-positive postmenopausal women with primary breast cancer (clinical stage ⩾T2, N0–1), from three sequential cohorts (cohort A of 40, cohort B of 40 and cohort C of 40 patients, respectively) based on different duration of the neoadjuvant letrozole. Biological markers such as ER, progesterone receptor, HER2 and Ki-67 expression were tested at diagnosis and at definitive surgery.

Results:

A total of 89 patients (75.4%) achieved an objective response with 44 (37.3%) clinical CRs and 45 (38.1%) partial responses. The clinical CRs were significantly observed in cohort C (23 out of 40 patients, 57.5%) and B (16 out of 38 patients, 42.1%) compared with cohort A (5 out of 40 patients, 12.5%) (P-value for trend <0.001). Letrozole induced a similar significant reduction in Ki-67 index after treatment in all cohorts. The pathCR rate was significantly more frequent in cohort C (7 out of 40 patients, 17.5%) than in cohort A (1 out of 40 patients, 2.5%) and B (2 out of 40 patients, 5.0%) (P-value for trend <0.04).

Conclusion:

One-year neoadjuvant letrozole therapy leads to a higher pathCR rate and may be the optimal length of drug exposure.     

Increase in response rate by prolonged treatment with neoadjuvant letrozole

Purpose The aim of this study was to investigate the potential benefits of prolonged treatment with neoadjuvant letrozole. Patients and Methods About 182 consecutive patients have been treated in Edinburgh with neoadjuvant letrozole for 3 months or longer and 63 patients have continued on letrozole beyond 3 months. Outcomes are reported. Results Of the 63 patients who continued on letrozole, 38 patients took letrozole for more than 1 year and 23 took letrozole for more than 24 months. The median reduction in clinical volume in the first 3 months in these 63 patients was 52%. Similar reductions in median clinical volume were seen between three to 6 months (50%), 6–12 months and 12–24 months (medians 37 and 33%, respectively). At 3 months 69.8% of the 182 patients had a partial or complete response. The response rate increased to 83.5% with prolonged letrozole treatment. Continuing letrozole beyond 3 months increased the number of women who initially required mastectomy or had locally advanced breast cancer who were subsequently suitable for breast conserving surgery from 60% (81/134) at 3 months to 72% (96/134). Thirty-three women remain on letrozole alone (man age at diagnosis 83 years) and at 3 years the median time to treatment failure has not been reached. Conclusion Continuing letrozole in responding patients beyond 3–4 months achieves further clinical reduction in tumour size. For elderly women with a short life expectancy letrozole alone may provide long-term disease control.     

Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma

Patients who have no residual invasive cancer following neoadjuvant chemotherapy for breast carcinoma have a better overall survival than those with residual disease. Many classification systems assessing pathological response to neoadjuvant chemotherapy include residual ductal carcinoma in situ (DCIS) only in the definition of pathological complete response. The purpose of this study was to investigate whether patients with residual DCIS only have the same prognosis as those with no residual invasive or in situ disease. A retrospective analysis of a prospectively maintained database identified 435 patients, who received neoadjuvant chemotherapy for operable breast cancer between February 1985 and February 2003. Of these, 30 (7%; 95% CI 5-9%) had no residual invasive disease or DCIS and 20 (5%; CI 3-7%) had residual DCIS only. With a median follow-up of 61 months, there was no statistical difference in disease-free survival, 80% (95% CI 60-90%) in those with no residual invasive or in situ disease and 61% (95% CI 35-80%) in those with DCIS only (P=0.4). No significant difference in 5-year overall survival was observed, 93% (95% CI 75-98%) in those with no residual invasive or in situ disease and 82% (95% CI 52-94%) in those with DCIS only (P=0.3). Due to the small number of patients and limited number of events in each group, it is not possible to draw definitive conclusions from this study. Further analyses of other databases are required to confirm our finding of no difference in disease-free and overall survival between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer.     

A trial-based cost-effectiveness analysis of letrozole followed by tamoxifen versus tamoxifen followed by letrozole for postmenopausal advanced breast cancer.

BACKGROUND: Third-generation aromatase inhibitors are being considered as an alternative to tamoxifen as first-line therapy for advanced breast cancer. These newer therapies are more expensive, and will gain greater acceptance if they can demonstrate cost-effectiveness. METHODS: Life table analyses are used to compare the costs and benefits [life years gained and quality-adjusted life years (QALYs) gained] of treating postmenopausal women with advanced breast cancer with first-line letrozole (with the option of second-line tamoxifen) compared with first-line tamoxifen (with the option of second-line letrozole). Patient-level data from a large clinical trial describes the effectiveness of the therapy options, clinicians estimate resource usage and utility values are obtained from the literature. RESULTS: The mean cost of providing first- and second-line hormonal therapy is pound 4765 if letrozole is the first-line therapy and pound 3418 if tamoxifen is provided first (a difference of pound 1347). However, patients receiving letrozole as first-line therapy gain an additional 0.228 life years, or 0.158 QALYs. The cost-effectiveness analysis found that first-line hormonal therapy with letrozole gains additional life years at a cost of pound 5917, whilst the cost per additional QALY gained is pound 8514. CONCLUSION: The strategy of letrozole as first-line hormonal therapy not only provides an opportunity for extending and improving patient's quality of life, but also is highly cost-effective compared with other generally accepted medical treatments.     

CT findings of breast cancer with clinically complete response following neoadjuvant chemotherapy--histological correlation

In breast cancer patients, several regimens of neoadjuvant chemotherapy have been developed in order to achieve prognostic advantages for individual patients. Though some percentages of breast cancer patients show clinically complete response to neoadjuvant chemotherapy, the histopathological specimens of these patients demonstrate a considerably high frequency of the existence of residual disease. In this study, we aimed to evaluate the therapeutic effect of neoadjuvant chemotherapy for breast cancer patients showing clinically complete response (cCR) to neoadjuvant chemotherapy, using thin-section (5 mm) helical CT (prone position) with bolus injection of contrast agent. Between April 1994 and March 2002, 9 patients with breast cancer showing cCR to the neoadjuvant chemotherapy, who had undergone thin-section CT study both before and following neoadjuvant chemotherapy, enrolled in the study. The mean age of the patients was 46.2 years and all of them were female. The clinical stages were, 8 patients in stage II, and one in stage IIIA. In the CT evaluation, residual disease was visualized in 5 out of the 9 patients. Histopathological examination disclosed the existence of residual cancers in 6 out of the 9 patients, but only non-invasive cancer was revealed in 1 out of the 6. As patients having residual disease composed only of non-invasive cancer are classified into the pathologically complete response group according to the WHO classification, 4 out of these 9 patients showing clinically complete response to the neoadjuvant chemotherapy were classified into pCR (pathologically complete response) group, and another 5 were classified into the pPR (pathologically partial response) group. As a result, the diagnostic accuracy of the second CT study performed after neoadjuvant chemotherapy was evaluated as 77.8%, with a sensitivity of 80.0%, a specificity of 75.0%, a positive predictive value (PPV) of 80.0%, and a negative predictive value (NPV) of 75.0%. Therefore, for precise evaluation of the neoadjuvant chemotherapeutic effect for breast cancer, thin-section CT studies are considered to be essential.     

从病理角度探讨乳腺癌的保乳疗法

目前,对于乳腺癌的治疗,采取保乳手术和保乳手术后并用放疗者越来越多,如何减少术后癌的复发已成为重要的研究课题。目前报道的保乳手术的术后复发率在1．3％～43％不等,除与切除范围、术后是否并用放射治疗及随访时间长短有关外,更重要的是与适应证的选择、手术标本断端的情况等有直接关系。保乳手术的术后复发,第一阶段的危险因素是癌的残留;第二阶段的危险因素是残留癌对放疗的敏感性欠佳。保乳手术或保乳疗法的成功与否,除手术外,还需病理、影像学诊断、放射线治疗及肿瘤内科等医生的密切配合,其中病理医师的工作非常重要。     

乳腺癌新辅助化疗效果的病理评估

乳腺癌新辅助化疗是乳腺癌标准化治疗方法之一,因此,新辅助治疗后的病理评估以及评估的标准化非常重要。不同病理评估标准的主要区别在于pCR的定义不同。现阶段一般把ypT₀/is ypN₀定义为pCR,即化疗后乳腺内可残留DCIS,但腋窝淋巴结内无癌细胞残留。笔者将着重介绍日本乳腺癌学会所采用的病理评估标准,并把该标准与美国MD Anderson癌症中心的残余肿瘤量(Residual Cancer Burden)系统、英国的Millar和Payne法,以及天津市肿瘤医院推荐的病理评估标准等进行比较。大量的临床研究表明,新辅助化疗后乳腺癌pCR者相比非pCR者,其DFS率和OS率均有明显提高。但是,pCR对于各种乳腺癌亚型的意义不尽相同,而pCR可能不是新辅助化疗的唯一预测因子。     

Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study

BackgroundTo measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid.Patients and methodsA phase 3 trial comparing tamoxifen, letrozole or letrozole + zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole + zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan.ResultsOut of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28–80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P < 0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole + zoledronic acid versus letrozole comparison (P < 0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P = 0.004 and 0.47, respectively).ConclusionsIn the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.     

A case of elderly breast cancer achieving partial response by letrozole with stable disease to anastrozole as neoadjuvant endocrine therapy

An 85-year-old postmenopausal woman had multiple lesions in her right breast. Core needle biopsy showed solidtubular carcinoma with positive hormone receptor (ER+++, PgR-). She refused surgery and was then treated with anastrozole as neoadjuvant endocrine therapy. After seven months of the treatment, all lesions were increased or unchanged. The clinical response was judged as stable disease. Letrozole was chosen for the next therapy. After ten months, reductions in the tumors were noted, and the clinical response was judged a partial response. No side effects were observed. These two drugs are nonsteroidal aromatase inhibitors, and it is considered there is a cross-resistance between them. However, several studies have revealed letrozole was significantly more potent than anastrozole in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in vivo. This may be related to a difference in effect between the two drugs. It is suggested that letrozole as second-line endocrine therapy may be effective for postmenopausal breast cancer even after anastrozole failure.     

Bone mineral density in breast cancer patients treated with adjuvant letrozole,tamoxifen, or sequences of letrozole and tamoxifen in the BIG 1-98 study (SAKK 21/07)

BackgroundThe risk of osteoporosis and fracture influences the selection of adjuvant endocrine therapy. We analyzed bone mineral density (BMD) in Swiss patients of the Breast International Group (BIG) 1-98 trial [treatment arms: A, tamoxifen (T) for 5 years; B, letrozole (L) for 5 years; C, 2 years of T followed by 3 years of L; D, 2 years of L followed by 3 years of T].Patients and methodsDual-energy X-ray absorptiometry (DXA) results were retrospectively collected. Patients without DXA served as control group. Repeated measures models using covariance structures allowing for different times between DXA were used to estimate changes in BMD. Prospectively defined covariates were considered as fixed effects in the multivariable models.ResultsTwo hundred and sixty-one of 546 patients had one or more DXA with 577 lumbar and 550 hip measurements. Weight, height, prior hormone replacement therapy, and hysterectomy were positively correlated with BMD; the correlation was negative for letrozole arms (B/C/D versus A), known osteoporosis, time on trial, age, chemotherapy, and smoking. Treatment did not influence the occurrence of osteoporosis (T score < -2.5 standard deviation).ConclusionsAll aromatase inhibitor regimens reduced BMD. The sequential schedules were as detrimental for bone density as L monotherapy.     

Ultrastructural study of rat mammary tumors and human breast cancer cells following treatment with tamoxifen

In order to predict the efficacy of hormonal therapy for breast cancer patients, early ultrastructural changes of rat mammary tumors and human breast cancer cells have been studied following treatment with tamoxifen. Following the treatment, complex nuclear bodies (CNB) were increased, and ring-shaped nucleoli were observed in both the rat mammary tumors and the human breast cancer cells. In the tamoxifen-treated human beast cancer patients, CNB increased, as estrogen receptor concentration rose. Shrunken nucleli and intranuclear rodlet were observed only in the tamoxifen-treated human cancer patients.     

Efficacy of tamoxifen following anastrozole ('Arimidex') compared with anastrozole following tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women

Anastrozole ('Arimidex') is indicated for the treatment of advanced breast cancer in postmenopausal women. Combined analysis of two international randomised, double-blind trials (n=1021) showed that in patients with hormone receptor-positive tumours, first-line treatment with anastrozole significantly prolonged the time to progression (TTP) compared with tamoxifen (median TTP: 10.7 versus 6.4 months, respectively; P=0.022). Second-line tamoxifen following anastrozole, or vice versa, in this trial population was unblinded. The treatments were crossed over and then efficacy was assessed using a questionnaire. Of 511 patients randomised to anastrozole, 137 (26.8%) received second-line tamoxifen. Questionnaire data were available for 119 patients; 58 (48.7%) gained clinical benefit (CB=complete+partial response (CR+PR)+(stable disease (SD) >/=24 weeks)), while 12 (10.1%) had an objective response (OR=CR+PR). Of 510 patients randomised to tamoxifen, 134 (26.3%) received second-line anastrozole. Questionnaire data from 95 patients showed that 54 (56.8%) gained CB and 7 of the patients gaining CB (7.4%) had an OR. Previous studies showed anastrozole is effective after first-line tamoxifen. These data show that the sequential administration of first-line anastrozole followed by tamoxifen provides effective use of these drugs in the treatment of postmenopausal women with advanced breast cancer.     

Pharmacoeconomic analysis of adjuvant therapy with exemestane, anastrozole, letrozole or tamoxifen in postmenopausal women with operable and estrogen receptor-positive breast cancer

Objective To compare the efficiency of adjuvant therapy with aromatase inhibitors or with tamoxifen in postmenopausal women with operable breast cancer and positive estrogen receptors. Material and methods A cost-utility analysis was performed based on a Markov model, from the Spanish National Health Care System perspective, comparing the treatment with exemestane (EXE: 25 mg/day) or tamoxifen (TAM: 20 mg/day) after 2–3 years of monotherapy with TAM; anastrozole (ANA, 1 mg/day) or TAM (20 mg/day) without previous TAM therapy; and letrozole (LET: 2.5 mg/day) or placebo after 5 years of monotherapy with TAM. The follow-up of a hypothetical cohort of women starting treatment at 63 years of age was simulated during 10 and 20 years. The probabilities of transition between health states and quality adjusted life years (QALYs) were obtained from the literature, and the unit costs (∈ corresponding to 2004) from a Spanish database. Results After 10 and 20 years of follow-up, more QALYs per patient would be gained with the EXE scheme (0.230–0.286 and 0.566–0.708, respectively) than with ANA (0.114 and 0.285) and LET (0.176 and 0.474). The cost of gaining one QALY was lower with the EXE scheme (50,801–62,522 ∈ and 28,849–35,371 ∈ respectively) than with ANA (104,272 ∈ and 62,477 ∈) and LET (91,210 ∈ and 49,460 ∈). The result was stable for the cost per life-year gained (LYG) and in the sensitivity analysis. Conclusions The EXE scheme after TAM is more cost-effective than the ANA and LET schemes.