Primary systemic therapy for operable breast cancer.

Eighty-eight patients presenting with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) have received primary systemic therapy. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume. Definitive locoregional surgery (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Response was observed in 24 (39%) of the 61 patients who received endocrine therapy; all 24 had tumours with an oestrogen receptor (ER) concentration of greater than or equal to 20 fmol mb-1 cytosol protein. Cytotoxic therapy was reserved for patients with tumours of ER concentration less than 20 fmol mg-1 cytosol protein (n = 27) or when endocrine therapy had failed (n = 20). Response was observed in 34 patients (72%). The overall survival rate at 3 years was 86%, with 81% remaining free from local relapse. We propose that the treatment policy outlined in this paper should now be tested against orthodox management by controlled randomised trial.     

Primary systemic therapy in operable breast cancer.

PURPOSE: Laboratory studies suggest that primary systemic therapy (PST) could improve control of micrometastatic disease and impact on overall survival (OS). This article examines the rationale for and preclinical and clinical data of PST in operable breast cancer and the potential role of intermediate biomarkers as predictive and/or prognostic factors for response and survival. DESIGN AND METHOD: We conducted an extensive literative review (including MEDLINE) on preclinical studies, single-arm feasibility studies, large randomized single- and multi-institutional trials, and laboratory correlate studies of PST in breast cancer. RESULTS: Small trials in locally advanced disease showed high initial rates of response and local control. Six randomized clinical trials (RCTs) of PST for palpable, operable breast cancer have been reported since 1991 (from 204 to 1,523 patients each). These data clearly show a small but significant (less than 10%) absolute increase in the use of breast-conservation treatment (BCT) with similar rates of local control. Although one study showed better disease-free survival (DFS) and another showed better OS, most studies did not show any survival advantage of primary versus adjuvant systemic therapy. Thus far, pathologic complete response seems to be the best predictor of survival, but clinical response assessment correlates poorly with pathologic response. Pilot studies demonstrated feasibility of procuring tissue at diagnosis and after treatment for assays of potential intermediate biomarkers. Initial data suggest a potential correlation between markers of proliferation and apoptosis and in vivo chemotherapy sensitivity. CONCLUSION: Thus far, RCTs of PST versus standard adjuvant therapy have not shown any clear benefit for DFS or OS in early breast cancer. Ongoing trials should determine if specific subsets of patients at risk would benefit from additional systemic therapy and the potential role of intermediate biomarkers in identifying such women. Although PST results in a small increase in the rate of BCT with similar rates of local control, current PST strategies should not replace standard adjuvant approaches. Rather, they represent an acceptable alternative to women with palpable, operable tumors and an excellent arena for clinical trials.     

Letrozole as primary medical therapy for locally advanced and large operable breast cancer

Aims. To investigate the efficacy of letrozole 2.5mg and 10mg used as primary neoadjuvant therapy for patients with locally advanced and large operable breast cancer. Patients and Methods. Twenty-four postmenopausal patients with locally advanced or large operable breast cancer were treated in two consecutive series with letrozole 2.5mg (n=12) or letrozole 10mg (n=12). Response at three months was measured by change in tumor volume according to WHO criteria (partial response was defined as a reduction in tumor volume 65%). Tumor volumes were assessed clinically, by ultrasound and mammography, and pathologically. Results. All 24 patients were estrogen receptor-positive, were considered receptor-rich, and mean age was 77.6 years and 71.6 years in the letrozole 2.5mg and 10mg treatment groups, respectively. There were five complete clinical responses and seven partial clinical responses in the patients treated with 2.5mg letrozole, and nine partial responses and three patients with stable disease in patients treated with 10mg letrozole. Assessed by ultrasound and mammography, the 12 patients treated with 2.5mg had one complete response, nine partial responses and two with no change. In the 12 patients treated with 10mg letrozole, imaging gave eight partial responses and four with no change. One patient treated with the 2.5mg dose had a complete clinical and pathological response. There was no significant difference between the two doses in effect on tumor volume, and no recordable side effects associated with either dose. Conclusion. Letrozole used in a neoadjuvant setting is highly effective, producing clinically beneficial reductions in tumor volume allowing all patients to have breast conserving surgery, and has an acceptable safety profile.     

Primary systemic therapy for operable breast cancer: a review of clinical trials and perspectives

Primary systemic therapy represents the standard of care for locally advanced breast cancer and has becoming an attractive alternative in earlier stages. A part from the proven advantage of increasing the rate of breast conservative surgery, the up front use of systemic therapy can allow for an in vivo test of treatment sensitivity, and response to primary treatment discriminates patients at different prognosis. This review will summarize the more relevant data on the preoperative treatment with chemotherapy, hormonal therapy and targeted agents.     

Commercialized multigene predictors of clinical outcome for breast cancer

In the past 5 years, a number of commercialized multigene prognostic and predictive tests have entered the complex and expanding landscape of breast cancer companion diagnostics. These tests have used a variety of formats ranging from the familiar slide-based assays of immunohistochemistry and fluorescence in situ hybridization to the nonmorphology-driven molecular platforms of quantitative multiplex real-time polymerase chain reaction and genomic microarray profiling. In this review, 14 multigene assays are evaluated as to their scientific validation, current clinical utility, regulatory approval status, and estimated cost-benefit ratio. Emphasis is placed on two tests: oncotype DX and MammaPrint. Current evidence indicates that the oncotype DX test has the advantages of earlier commercial launch, wide acceptance for payment by third-party payors in the U.S., ease of use of formalin-fixed paraffin-embedded tissues, recent listing by the American Society of Clinical Oncology Breast Cancer Tumor Markers Update Committee as recommended for use, continuous scoring system algorithm, ability to serve as both a prognostic test and predictive test for certain hormonal and chemotherapeutic agents, demonstrated cost-effectiveness in one published study, and a high accrual rate for the prospective validation clinical trial (Trial Assigning Individualized Options for Treatment). The MammaPrint assay has the advantages of a 510(k) clearance by the U.S. Food and Drug Administration, a larger gene number, which may enhance further utility, and a potentially wider patient eligibility, including lymph node-positive, estrogen receptor (ER)-negative, and younger patients being accrued into the prospective trial (Microarray in Node-Negative Disease May Avoid Chemotherapy). A number of other assays have specific predictive goals that are most often focused on the efficacy of tamoxifen in ER-positive patients, such as the two-gene ratio test and the cytochrome P450 CYP2D6 genotyping assay.     

Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients.

The aim of this study was to evaluate pretreatment clinical features and biological markers together with changes in these factors as predictors of response and relapse in patients receiving tamoxifen for primary breast cancer. Fine-needle aspiration cytology of the primary breast cancer was performed before tamoxifen treatment in 54 patients and repeated after therapy on day 14, day 60, or on both days in a subset of 35 patients. These samples were evaluated for estrogen receptor (ER), progesterone receptor (PgR), Ki67, S-phase fraction and ploidy. The overall response to tamoxifen was 57% (31 of 54 patients). Pretreatment ER and PgR significantly predicted for response by univariate analysis (P < 0.0001 and P < 0.003, respectively). By multivariate analysis, ER expression was the only independent predictor of response, and it was associated with 27 times the likelihood of response (95% confidence interval, 6-136). Increase in PgR and decrease in Ki67 on day 14 significantly predicted for response to tamoxifen (P < 0.03 and P < 0.04, respectively). Lack of ER, clinical node-positive disease, and failure to decrease Ki67 on day 14 were significantly associated with increased risk of relapse (P < 0.05). By multivariate analysis, ER expression was the only independent predictor of relapse (P < 0.005). Pretreatment and early changes in molecular marker expression may assist in the prediction of response and clinical outcome in primary breast cancer patients receiving tamoxifen.     

Recent advances in systemic therapy. New diagnostics and biological predictors of outcome in early breast cancer

The key to optimising our approach in early breast cancer is to individualise care. Each patient has a tumour with innate features that dictate their chance of relapse and their responsiveness to treatment. Often patients with similar clinical and pathological tumours will have markedly different outcomes and responses to adjuvant intervention. These differences are encoded in the tumour genetic profile. Effective biomarkers may replace or complement traditional clinical and histopathological markers in assessing tumour behaviour and risk. Development of high-throughput genomic technologies is enabling the study of gene expression profiles of tumours. Genomic fingerprints may refine prediction of the course of disease and response to adjuvant interventions. This review will focus on the role of multiparameter gene expression analyses in early breast cancer, with regards to prognosis and prediction. The prognostic role of genomic signatures, particularly the Mammaprint and Rotterdam signatures, is evolving. With regard to prediction of outcome, the Oncotype Dx multigene assay is in clinical use in tamoxifen treated patients. Extensive research continues on predictive gene identification for specific chemotherapeutic agents, particularly the anthracyclines, taxanes and alkylating agents.     

A 2-month cisplatin-epirubicin-paclitaxel (PET) weekly combination as primary systemic therapy for large operable breast cancer: a phase II study.

PURPOSE: The present study aimed to define the antitumor activity of eight cisplatin-epirubicin-paclitaxel (PET) weekly cycles with granulocyte colony-stimulating factor (G-CSF) support in patients with large operable breast cancer. METHODS: Operable breast cancer (T2-3 N0-1; T >3 cm) patients received eight preoperative weekly cycles of cisplatin 30 mg/m2, epirubicin 50 mg/m2 and paclitaxel 120 mg/m2, with G-CSF (5 microg/kg, days 3-5) support. RESULTS: Sixty-three patients (T2/T3=30/33; N0/N+=8/55) were enrolled. Thirty-one clinical complete (49%) and 30 partial (48%) responses were recorded, giving a 97% response rate (95% confidence interval 89% to 100%). Breast-sparing surgery was performed in 32/63 (51%) patients. At pathological assessment, 28 patients (45%) showed absence of invasive residual disease in breast and 34 (55%) had negative axilla. In 20 women (32%) both breast and axilla were found to be disease-free. At a 23-month median follow-up (range 4-63), only eight relapses and two deaths had occurred, with the 4-year projected relapse-free and overall survival being 59% and 95%, respectively. Grade 3-4 neutropenia and anemia occurred in 24% and 5% of patients, respectively. Emesis, diarrhea and mucositis were the main non-hematological toxicities; however, only nine (14%) patients experienced one or more episodes of severe non-hematological toxicity. Peripheral neuropathy was frequent, but never severe. CONCLUSIONS: A 2-month weekly treatment with PET represents a well tolerated and highly effective approach in large operable breast cancer patients. In spite of the short duration of chemotherapy, one-third of patients achieved a complete eradication of the tumor in both breast and axilla.     

Primary medical therapy for operable breast cancer

Fifty-seven patients with large but potentially operable primary breast cancer were treated with primary medical therapy rather than initial mastectomy, using chemotherapy (15) or endocrine therapy (42) with the tumour remaining in situ. Of patients treated with chemotherapy, one (7%) achieved a complete remission, and eight (53%) a partial response (overall response rate 60%). Only one patient had progressive disease while on chemotherapy. Of patients who received endocrine therapy, one (2%) achieved a complete response, and 19 (45%) a partial response (overall response rate 47%). Two patients progressed on endocrine therapy. Only 10 patients have so far had a subsequent mastectomy (18%), and 17 (30%) have had radiotherapy and/or conservative surgery. The rest are still on medical therapy.With a median follow-up of 19 months (range 6–42 months) only two patients have had a local recurrence after being disease-free and none have developed uncontrollable local recurrence. Eight (14%) have developed distant metastases and four (7%) have died of metastatic disease.Primary medical therapy may offer an effective alternative to mastectomy for patients with operable breast carcinomas too large for conservative surgery and merits further study.     

Adjuvant endocrine therapy for operable breast cancer

A brief resume of adjuvant endocrine therapy for operable breast cancer is given. This was first suggested in the 1930's but has only become accepted in the last 10-15 years. The reason for the lack of survival benefit in the first randomised trial, which began in 1948 in Manchester, was thought to be due to the increasing use of hormone therapy for metastases. Revival of interest came with the survival gain reported in the Toronto ovarian trial and the success in post-menopausal patients of the non-toxic anti-oestrogen tamoxifen. The different dose schedules used in the various large tamoxifen trials could explain the confusingly variable results in the literature. Combined analysis of trial results indicates that CMF is the adjuvant therapy of choice for pre-menopausal patients but this therapy may in part be acting through the ovaries. The Scottish and NATO trials have an overall survival advantage from adjuvant tamoxifen, even in pre-menopausal patients, and both have shown results to be independent of oestrogen receptor (ER) status. Whether the extra 3 years given in Scotland adds an additional benefit over the more commonly used 2-year course is uncertain. A statistically invalid look at selected data in the Scottish trial suggests that, in ER positive cases, post-relapse tamoxifen may have as great an effect on total survival as adjuvant use, a finding similar to that suggested by the first ovarian ablation trial and one requiring continued review.     

Understanding the utility of adjuvant systemic therapy for primary breast cancer.

PURPOSE: Physicians and patients require quantitative information on the expected benefits of adjuvant therapy for primary breast cancer to make appropriate treatment decisions. To date, there has not been any widely available method for estimating the benefits from adjuvant systemic therapy, in terms of long-term disease-free survival probabilities, in patients with primary breast cancer. METHODS: Baseline prognostic information for primary breast cancer patients was estimated by asking 11 breast cancer specialists to complete a questionnaire on baseline prognosis and then using mean values. Data on the relative benefits of adjuvant therapy were culled from systematic reviews and randomized controlled trials. A computer algorithm was developed to calculate 10-year absolute outcome data. Results from this evaluation were compared with a previously described actuarial algorithm. RESULTS: Individual prognostic estimates varied within a group of breast cancer specialists, but mean values of their estimates closely followed published data. Translation of expected benefits of adjuvant therapy from relative to absolute terms was performed with a simple computer algorithm. The data were translated into tabular forms to facilitate user-friendly clinical use. CONCLUSION: The provided data should facilitate a better understanding of the absolute magnitude of benefit for available systemic adjuvant therapies in individual women with primary breast cancer. This should allow patients to make more informed decisions about their options.     

可手术乳腺癌的新辅助全身治疗

新辅助全身治疗(neoadjuvant systemic treatment, NST)也称术前全身治疗。以全身治疗为原发性乳腺癌的首治方法兴起于上世纪70年代,其初衷是为了解决不可切除或切除困难的局部晚期乳腺癌(locally advanced breast cancer,LABC)和炎性乳腺     

预测大肠癌化疗疗效的分子或基因指标

用于治疗大肠癌的药物主要有氟尿嘧啶、卡培他宾、依立替康、奥沙利铂、昔妥单抗、贝伐单抗,使大肠癌的化疗有效率明显提高,病人中位生存时间明显延长。但大肠癌化疗中原发和获得性耐药现象很普遍。一些分子或基因指标有可能预测大肠患者能否从辅助化疗或姑息化疗中获益。这篇综述主要回顾预测大肠癌化疗药物疗效的分子和基因指标,分析其联系,从而指导临床按个体化原则用药。     

可手术乳腺癌术前全身治疗存在的问题及未来方向

乳腺癌术前全身治疗(preoperative systemic therapy,PST)也称为新辅助全身治疗,包括化疗、内分泌治疗和生物学靶向治疗,是乳腺癌综合治疗的重要组成部分.     

Intratumoral molecular or genetic markers as predictors of clinical outcome with chemotherapy in colorectal cancer

Identification of molecular markers at either the intragenic, chromosomal, mRNA, or protein level that might predict whether colorectal cancer patients are likely to benefit from adjuvant or palliative therapy is a high priority. The majority of clinical studies addressing this issue, particularly those done in the adjuvant setting, analyzed tumor samples from patients treated in the era when 5-fluorouracil (5-FU) alone or combined with leucovorin or levamisole were the mainstay of therapy. This review highlights some of the intratumoral molecular markers that may have importance as predictors of benefit with 5-FU-based therapy. Although the goal of these investigations is to one day permit selection of therapy for an individual patient based on the tumor phenotype, prospective studies have yet to be conducted that test whether selection of therapy based on molecular markers results in an improved outcome.     

Long-term clinical outcome of oestrogen receptor-positive operable primary breast cancer in older women: a large series from a single centre

Introduction:

A Cochrane review of seven randomised trials (N=1571) comparing surgery and primary endocrine therapy (PET) (oestrogen receptor (ER) unselected) shows no difference in overall survival (OS). We report outcome of a large series with ER-positive (ER+) early invasive primary breast cancer.

Methods:

Between 1973 and 2009, 1065 older (⩾70 years) women (median age 78 years (70–99)) had either surgery (N=449) or PET (N=616) as initial treatment.

Results:

At 49-month median follow-up (longest 230 months), the 5-year breast cancer-specific survival (BCSS) and OS were 90 and 62%, respectively. Majority (74.2%) died from causes other than breast cancer. The rates (per annum) of local/regional recurrence (<1%) (following surgery), contralateral tumour (<1%) and metastases (<3%) were low. For patients on PET, 97.9% achieved clinical benefit (CB) at 6 months, with median time to progression of 49 months (longest 132 months) and significantly longer BCSS when compared with those who progressed (P<0.001). All patients with strongly ER+ (H-score >250) tumours achieved CB and had better BCSS (P<0.01). Patients with tumours having an H-score >250 were found to have equivalent BCSS regardless of treatment (surgery or PET; P=0.175), whereas for those with H-score ⩽250, surgery produced better outcome (P<0.001).

Conclusion:

Older women with ER+ breast cancer appear to have excellent long-term outcome regardless of initial treatment. Majority also die from non-breast cancer causes. Although surgery remains the treatment of choice, patients with ER-rich (H-score >250) tumours tend to do equally well when treated by PET. This should be taken into account when therapies are considered.     

可手术乳腺癌的综合治疗进展

乳腺癌已被公认为全身性疾病,综合治疗已取得肯定效果并积累了丰富经验.对目前综合治疗的现状,包括方案的选择及综合治疗应用的方法、时机等进行综述.