Monica Castiglione-Gertsch

Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013

The 13th St Gallen International Breast Cancer Conference (2013) Expert Panel reviewed and endorsed substantial new evidence on aspects of the local and regional therapies for early breast cancer, supporting less extensive surgery to the axilla and shorter durations of radiation therapy. It refined its earlier approach to the classification and management of luminal disease in the absence of amplification or overexpression of the Human Epidermal growth factor Receptor 2 (HER2) oncogene, while retaining essentially unchanged recommendations for the systemic adjuvant therapy of HER2-positive and ‘triple-negative’ disease. The Panel again accepted that conventional clinico-pathological factors provided a surrogate subtype classification, while noting that in those areas of the world where multi-gene molecular assays are readily available many clinicians prefer to base chemotherapy decisions for patients with luminal disease on these genomic results rather than the surrogate subtype definitions. Several multi-gene molecular assays were recognized as providing accurate and reproducible prognostic information, and in some cases prediction of response to chemotherapy. Cost and availability preclude their application in many environments at the present time. Broad treatment recommendations are presented. Such recommendations do not imply that each Panel member agrees: indeed, among more than 100 questions, only one (trastuzumab duration) commanded 100% agreement. The various recommendations in fact carried differing degrees of support, as reflected in the nuanced wording of the text below and in the votes recorded in supplementary Appendix S1, available at Annals of Oncology online. Detailed decisions on treatment will as always involve clinical consideration of disease extent, host factors, patient preferences and social and economic constraints.

Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98

PURPOSE Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results. PATIENTS AND METHODS Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point. RESULTS At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure. CONCLUSION The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.

Prognostic and Predictive Value of Centrally Reviewed Expression of Estrogen and Progesterone Receptors in a Randomized Trial Comparing Letrozole and Tamoxifen Adjuvant Therapy for Postmenopausal Early Breast Cancer: BIG 1-98

PURPOSE To evaluate locally versus centrally assessed estrogen (ER) and progesterone (PgR) receptor status and the impact of PgR on letrozole adjuvant therapy compared with tamoxifen in postmenopausal women with early breast cancer. PATIENTS AND METHODS Breast International Group (BIG) 1-98 randomly assigned 8,010 patients to four arms comparing letrozole and tamoxifen with sequences of each agent. The Central Pathology Office received material for 6,549 patients (82%), of which 79% were assessable (6,291 patients). Prognostic and predictive value of both local and central hormone receptor expression on disease-free survival (DFS) were evaluated among 3,650 assessable patients assigned to the monotherapy arms. Prognostic value and the treatment effect were estimated for centrally assessed ER and PgR expression levels using the Subpopulation Treatment Effect Pattern Plot. RESULTS Central review confirmed 97% of tumors as hormone receptor-positive (ER and/or PgR > or =10%). Of 105 tumors locally ER-negative, 73 were found to have more than 10% positive cells, and eight had 1% to 9%. Of 6,100 tumors locally ER positive, 66 were found to have no staining, and 54 had only 1% to 9%. Discordance was more marked for PgR than ER. Patients with tumors reclassified centrally as ER-negative, or as hormone receptor-negative, had poor DFS. Centrally assessed ER and PgR showed prognostic value. Among patients with centrally assessed ER-expressing tumors, letrozole showed better DFS than tamoxifen, irrespective of PgR expression level. CONCLUSION Central review changed the assessment of receptor status in a substantial proportion of patients, and should be performed whenever possible in similar trials. PgR expression did not affect the relative efficacy of letrozole over tamoxifen.

Burdens and Benefits of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil and Tamoxifen for Elderly Patients With Breast Cancer: The International Breast Cancer Study Group Trial VII

PURPOSE Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII. PATIENTS AND METHODS Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m(2) orally days 1 to 14), methotrexate (40 mg/m(2) intravenous days 1 and 8), and fluorouracil (600 mg/m(2) intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years. RESULTS Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P =.004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P =.0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P =.99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P =.008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received. CONCLUSION CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.

Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer?

BACKGROUND The prognosis of breast cancer in very young women is generally considered to be unfavourable. Therefore, the outcome of adjuvant therapy was analysed in a population of young (<35 years) premenopausal patients treated in four randomised controlled trials. METHODS Between 1978 and 1993 the International Breast Cancer Study Group (IBCSG) treated 3700 premenopausal and perimenopausal patients with various timing and duration of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF with or without low-dose prednisone and oophorectomy). 314 of these women were less than 35 years old at randomisation. FINDINGS Relapse and death occurred earlier and more often in younger (<35 years) than in older (> or = 35) patients with a 10 year disease-free survival of 35% (SE 3) versus 47% (1) (hazard ratio 1.41 [95% CI 1.22-1.62], p<0.001) and overall survival of 49% (3) versus 62% (1) (1.50 [1.28-1.77], p<0.001). Younger patients with oestrogen-receptor positive tumours had a significantly worse disease-free survival than younger patients with oestrogen-receptor negative tumours. By contrast, among older patients the disease-free survival was similar irrespective of oestrogen-receptor status. INTERPRETATION Young premenopausal breast cancer patients treated with adjuvant CMF chemotherapy had higher risk of relapse and death than older premenopausal patients, especially if their tumours expressed oestrogen receptors. The endocrine effects of chemotherapy alone are insufficient for the younger age group and these patients should strongly consider additional endocrine therapies (tamoxifen or ovarian ablation) if their tumours express oestrogen receptors.

Prognostic and Predictive Value of Centrally Reviewed Ki-67 Labeling Index in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Results From Breast International Group Trial 1-98 Comparing Adjuvant Tamoxifen With Letrozole

PURPOSE To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

Distinct Clinical and Prognostic Features of Infiltrating Lobular Carcinoma of the Breast: Combined Results of 15 International Breast Cancer Study Group Clinical Trials

PURPOSE To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local treatment, and patterns of recurrence. PATIENTS AND METHODS Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types. RESULTS Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)-positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01). CONCLUSION ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.

Effect of Pregnancy on Overall Survival After the Diagnosis of Early-Stage Breast Cancer

PURPOSE To evaluate the impact of subsequent pregnancy on the prognosis of patients with early breast cancer. PATIENTS AND METHODS One hundred eight patients who became pregnant after diagnosis of early-stage breast cancer were identified in institutions participating in International Breast Cancer Study Group (IBCSG) studies. Fourteen had relapse of breast cancer before their first subsequent pregnancy. The remaining 94 patients (including eight who relapsed during pregnancy) formed the study group reported here. A comparison group of 188 was obtained by randomly selecting two patients, matched for nodal status, tumor size, age, and year of diagnosis from the IBCSG database, who were free of relapse for at least as long as the time between breast cancer diagnosis and completion of pregnancy for each pregnant patient. Survival comparison used Cox proportional hazards regression models. RESULTS Overall 5- and 10-year survival percentages (+/- SE) measured from the diagnosis of early-stage breast cancer among the 94 study group patients were 92% +/- 3% and 86% +/- 4%, respectively. For the matched comparison group survival was 85% +/- 3% at 5 years and 74% +/- 4% at 10 years (risk ratio, 0.44; 95% confidence interval, 0.21 to 0.96; P =.04). CONCLUSION Subsequent pregnancy does not adversely affect the prognosis of early-stage breast cancer. The superior survival seen in this and other controlled series may merely reflect a healthy patient selection bias, but is also consistent with an antitumor effect of the pregnancy.

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 studies.

Phase II Study of Capecitabine and Oxaliplatin in First- and Second-Line Treatment of Advanced or Metastatic Colorectal Cancer

PURPOSE To determine the efficacy and tolerability of combining oxaliplatin with capecitabine in the treatment of advanced nonpretreated and pretreated colorectal cancer. PATIENTS AND METHODS Forty-three nonpretreated patients and 26 patients who had experienced one fluoropyrimidine-containing regimen for advanced colorectal cancer were treated with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) bid on days 1 to 14 every 3 weeks. Patients with good performance status (World Health Organization grade 0 to 1) were accrued onto two nonrandomized parallel arms of a phase II study. RESULTS The objective response rate was 49% (95% confidence interval [CI], 33% to 65%) for nonpretreated and 15% (95% CI, 4% to 35%) for pretreated patients. The main toxicity of this combination was diarrhea, which occurred at grade 3 or 4 in 35% of the nonpretreated and 50% of the pretreated patients. Grade 3 or 4 sensory neuropathy, including laryngopharyngeal dysesthesia, occurred in 16% of patients on both cohorts. Capecitabine dose reductions were necessary in 26% of the nonpretreated and 45% of the pretreated patients in the second treatment cycle. The median overall survival was 17.1 months and 11.5 months, respectively. CONCLUSION Combining capecitabine and oxaliplatin yields promising activity in advanced colorectal cancer. The main toxicity is diarrhea, which is manageable with appropriate dose reductions. On the basis of our toxicity experience, we recommend use of capecitabine in combination with oxaliplatin 130 mg/m(2) at an initial dose of 1,250 mg/m(2) bid in nonpretreated patients and at a dose of 1,000 mg/m(2) bid in pretreated patients.