A última palavra em terapia adjuvante para câncer de mama

Adjuvant systemic therapy has been shown to reduce relapses in treated women and to prolong their survival. This is true for all studied subpopulations. Multidrug chemotherapy for the duration of 6 months with the addition of tamoxifen for patients with hormone receptorpositive tumors and for the premenopausal patients, and tamoxifen or short-term chemotherapy with long-term tamoxifen for the postmenopausal patients represent the treatments of choice to reduce the risk of relapse. In general, patients should be treated with a much more individualized adjuvant therapy program than is currently being prescribed. Current practice is based largely on estimates of average chemotherapy effects obtained from patients with heterogeneous disease and menopausal status characteristics. Some of the open questions relate to i) the definition of the populations for which risk of relapse justifies therapy, and ii) the optimal way of using available therapies might find answer from ongoing research in the next future. The modest but real improvement of the prognosis in operable breast cancer was exclusively obtained by means of clinical trials, and it is mandatory that participation in programs of clinical research become medically and socially the treatment of choice for patients and for their doctors.Estudos têm demonstrado que a terapia sistêmica adjuvante diminui os relapsos em mulheres submetidas a tratamento e melhora a sua sobrevida. Isto se verifica para todas as sub-populações estudadas. A quimioterapia com múltiplas drogas, com duração de 6  meses e adição de tamoxifeno para pacientes com tumores positivos para receptores de hormônios e para pacientes pré-menopausa, e de tamoxifeno ou quimioterapia de curto prazo com tamoxifeno a longo prazo para pacientes pós-menopausa representam os tratamentos de escolha para reduzir os riscos de relapso. Em geral, os pacientes devem ser tratados com programas de terapias adjuvantes mais individualizados do que o que está sendo feito na prática atual. A prática atual é largamente baseada em estimativas de efeitos médios de quimioterapia obtidos com pacientes com doenças heterogêneas e características de quadro de menopausa. Algumas das questões que precisam ser respondidas são: i) a definição das populações de risco para relapso justifica a terapia e ii) a maneira mais otimizada de utilizar as terapias disponíveis poderá ser encontrada nas pesquisas que estarão sendo desenvolvidas em um futuro próximo. A melhora modesta, mas real, no prognóstico de câncer operável foi obtida exclusivamente através de testes clínicos. É necessário, ainda, que a participação em programas de pesquisas clínicas seja o tratamento de escolha em termos médicos e sociais para pacientes e seus médicos.

Ki-67 Expression in Breast Cancer; Its Association with Grading Systems, Clinical Parameters and Other Prognostic Factors -- A Surrogate Marker?

BACKGROUND. The number of mitoses and, thus, the proliferative capacity of a tumor is one of the most crucial variables for tumor grading. The Ki-67 nuclear antigen may be considered as an alternative to mitotic counts in grading schemes and as a single parameter that can be used in fine-needle aspirates and small biopsies. METHODS. Immunohistochemistry using the anti-Ki-67 antibody MIB-1 was performed on 434 breast carcinoma specimens from the International Breast Cancer Study Group (formerly Ludwig) Trial V. Three groups based on Ki-67 percent were used to replace the mitotic counts component in the Nottingham grade (NHG) to produce the Nottingham/Ki-67 grade (NKG) and to assess Ki-67 as a single parameter. RESULTS. In both the lymph node positive subgroup and the lymph node negative subgroup, the NKG and Ki-67 group was correlated significantly with Bloom– Richardson grade (BRG), NHG, and Nottingham type. Tumor size in the lymph node negative cohort and estrogen receptor status, progesterone receptor status, and c-erbB-2 expression in the lymph node positive cohort also were correlated significantly with NKG. Ki-67 percentage was correlated significantly with c-erbB-2 expression in the lymph node positive cohort only. NKG was similar to BRG and NHG when it was evaluated for prognostic significance. Patients with higher categoric Ki-67 percentages had worse overall and disease free survival in all groups except for the untreated, lymph node negative group. CONCLUSIONS. Ki-67 detection represents a valuable tool and is a good objective substitute for mitotic counts when used in a grading system. When it is used alone, Ki-67 detection provides valuable information, although it is necessary to combine this with other parameters in the study of core biopsies and fine-needle aspirates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91948/1/2003 Cancer Ki-67 Expression in Breast Carcinoma.pd

Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX

Introduction: The prognostic significance of p53 protein expression in early breast cancer remains uncertain, with some but not all studies finding an association with poorer outcomes. Estrogen receptor (ER) expression is both a positive prognostic marker and predictive of response to endocrine therapies. The relationship between these biomarkers is unknown. Methods: We constructed tissue microarrays (TMAs) from available pathological material from 1113 patients participating in two randomized clinical trials comparing endocrine therapy alone versus chemo-endocrine therapy in node-negative breast cancer. Expression of p53 defined as >10% positive nuclei was analyzed together with prior immunohistochemical assays of ER performed at central pathological review of whole tumor sections. Results: ER was present (i.e. >1% positive tumor cell nuclei) in 80.1% (880/1092). p53 expression was significantly more frequent when ER was absent, 125/212 (59%) than when ER was present, 171/880 (19%), p <0.0001. A significant qualitative interaction was observed such that p53 expression was associated with better disease-free survival (DFS) and overall survival (OS) among patients whose tumors did not express ER, but worse DFS and OS among patients whose tumors expressed ER. The interaction remained significant after allowance for pathologic variables, and treatment. Similar effects were seen when luminal and non-luminal intrinsic subtypes were compared. Conclusions: Interpretation of the prognostic significance of p53 expression requires knowledge of concurrent expression of ER. The reason for the interaction between p53 and ER is unknown but may reflect qualitatively different p53 mutations underlying the p53 expression in tumors with or without ER expression. Trial registration Current Controlled Trials ACTRN12607000037404 (Trial VIII) and ACTRN12607000029493 (Trial IX)

Re-evaluating Adjuvant Breast Cancer Trials: Assessing Hormone Receptor Status by Immunohistochemical Versus Extraction Assays

Background: Tumor levels of steroid hormone receptors, a factor used to select adjuvant treatment for early-stage breast cancer, are currently determined with immunohistochemical assays. These assays have a discordance of 10%-30% with previously used extraction assays. We assessed the concordance and predictive value of hormone receptor status as determined by immunohistochemical and extraction assays on specimens from International Breast Cancer Study Group Trials VIII and IX. These trials predominantly used extraction assays and compared adjuvant chemoendocrine therapy with endocrine therapy alone among pre- and postmenopausal patients with lymph node-negative breast cancer. Trial conclusions were that combination therapy provided a benefit to pre- and postmenopausal patients with estrogen receptor (ER)-negative tumors but not to ER-positive postmenopausal patients. ER-positive premenopausal patients required further study. Methods: Tumor specimens from 571 premenopausal and 976 postmenopausal patients on which extraction assays had determined ER and progesterone receptor (PgR) levels before randomization from October 1, 1988, through October 1, 1999, were re-evaluated with an immunohistochemical assay in a central pathology laboratory. The endpoint was disease-free survival. Hazard ratios of recurrence or death for treatment comparisons were estimated with Cox proportional hazards regression models, and discriminatory ability was evaluated with the c index. All statistical tests were two-sided. Results: Concordance of hormone receptor status determined by both assays ranged from 74% (κ = 0.48) for PgR among postmenopausal patients to 88% (κ = 0.66) for ER in postmenopausal patients. Hazard ratio estimates were similar for the association between disease-free survival and ER status (among all patients) or PgR status (among postmenopausal patients) as determined by the two methods. However, among premenopausal patients treated with endocrine therapy alone, the discriminatory ability of PgR status as determined by immunohistochemical assay was statistically significantly better (c index = 0.60 versus 0.51; P = .003) than that determined by extraction assay, and so immunohistochemically determined PgR status could predict disease-free survival. Conclusions: Trial conclusions in which ER status (for all patients) or PgR status (for postmenopausal patients) was determined by immunohistochemical assay supported those determined by extraction assays. However, among premenopausal patients, trial conclusions drawn from PgR status differed—immunohistochemically determined PgR status could predict response to endocrine therapy, unlike that determined by the extraction assa

Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02-98 Randomized Trial

Background Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. Methods Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. Results Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). Conclusions Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherap

Predictive Value of Tumor Ki-67 Expression in Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studie

Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015

The 14th St Gallen International Breast Cancer Conference (2015) reviewed new evidence on locoregional and systemic therapies for early breast cancer. This manuscript presents news and progress since the 2013 meeting, provides expert opinion on almost 200 questions posed to Consensus Panel members, and summarizes treatment-oriented classification of subgroups and treatment recommendation

A última palavra em terapia adjuvante para câncer de mama

Adjuvant systemic therapy has been shown to reduce relapses in treated women and to prolong their survival. This is true for all studied subpopulations. Multidrug chemotherapy for the duration of 6 months with the addition of tamoxifen for patients with hormone receptorpositive tumors and for the premenopausal patients, and tamoxifen or short-term chemotherapy with long-term tamoxifen for the postmenopausal patients represent the treatments of choice to reduce the risk of relapse. In general, patients should be treated with a much more individualized adjuvant therapy program than is currently being prescribed. Current practice is based largely on estimates of average chemotherapy effects obtained from patients with heterogeneous disease and menopausal status characteristics. Some of the open questions relate to i) the definition of the populations for which risk of relapse justifies therapy, and ii) the optimal way of using available therapies might find answer from ongoing research in the next future. The modest but real improvement of the prognosis in operable breast cancer was exclusively obtained by means of clinical trials, and it is mandatory that participation in programs of clinical research become medically and socially the treatment of choice for patients and for their doctors.Estudos têm demonstrado que a terapia sistêmica adjuvante diminui os relapsos em mulheres submetidas a tratamento e melhora a sua sobrevida. Isto se verifica para todas as sub-populações estudadas. A quimioterapia com múltiplas drogas, com duração de 6  meses e adição de tamoxifeno para pacientes com tumores positivos para receptores de hormônios e para pacientes pré-menopausa, e de tamoxifeno ou quimioterapia de curto prazo com tamoxifeno a longo prazo para pacientes pós-menopausa representam os tratamentos de escolha para reduzir os riscos de relapso. Em geral, os pacientes devem ser tratados com programas de terapias adjuvantes mais individualizados do que o que está sendo feito na prática atual. A prática atual é largamente baseada em estimativas de efeitos médios de quimioterapia obtidos com pacientes com doenças heterogêneas e características de quadro de menopausa. Algumas das questões que precisam ser respondidas são: i) a definição das populações de risco para relapso justifica a terapia e ii) a maneira mais otimizada de utilizar as terapias disponíveis poderá ser encontrada nas pesquisas que estarão sendo desenvolvidas em um futuro próximo. A melhora modesta, mas real, no prognóstico de câncer operável foi obtida exclusivamente através de testes clínicos. É necessário, ainda, que a participação em programas de pesquisas clínicas seja o tratamento de escolha em termos médicos e sociais para pacientes e seus médicos.