Mary-Ann Lindsay

Alteration of Topoisomerase II–Alpha Gene in Human Breast Cancer: Association With Responsiveness to Anthracycline-Based Chemotherapy

PURPOSE Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene encoding an enzyme that is a major target of anthracyclines. This study was designed to evaluate whether TOP2A gene alterations may predict incremental responsiveness to anthracyclines in some breast cancers. METHODS A total of 4,943 breast cancers were analyzed for alterations in TOP2A and HER2. Primary tumor tissues from patients with metastatic breast cancer treated in a trial of chemotherapy plus/minus trastuzumab were studied for amplification/deletion of TOP2A and HER2 as a test set followed by evaluation of malignancies from two separate, large trials for changes in these same genes as a validation set. Association between these alterations and clinical outcomes was determined. RESULTS Test set cases containing HER2 amplification treated with doxorubicin and cyclophosphamide (AC) plus trastuzumab, demonstrated longer progression-free survival compared to those treated with AC alone (P = .0002). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar improvement in survival (P = .004). Conversely, for patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in a larger validation set, where HER2/TOP2A coamplification was again associated with longer survival when only anthracycline-containing chemotherapy was used for treatment compared with outcome in HER2-positive cancers lacking TOP2A coamplification. CONCLUSION In a study involving nearly 5,000 breast malignancies, both test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of an incremental response to anthracycline-based chemotherapy. Absence of HER2/TOP2A coamplification may indicate a more restricted efficacy advantage for breast cancers than previously thought.

Phase III Study of Doxorubicin/Cyclophosphamide With Concomitant Versus Sequential Docetaxel As Adjuvant Treatment in Patients With Human Epidermal Growth Factor Receptor 2–Normal, Node-Positive Breast Cancer: BCIRG-005 Trial

PURPOSE Anthracyclines, taxanes, and alkylating agents are among the most active agents in treatment of adjuvant breast cancer (BC), but the optimal schedule for their administration is unknown. We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide (AC) followed by docetaxel (ie, AC>T) with the combination regimen of TAC. PATIENTS AND METHODS Women with node-positive, human epidermal growth factor receptor 2-nonamplified, operable BC were stratified by number of axillary nodes and hormone receptor status and were randomly assigned to adjuvant chemotherapy with six cycles of TAC (75/50/500 mg/m² every 3 weeks) or four cycles of AC (60/600 mg/m² every 3 weeks) followed by four doses of docetaxel at 100 mg/m² every 3 weeks (AC>T). After completion of chemotherapy, radiation therapy was given as indicated, and patients with hormone receptor (HR) -positive disease received adjuvant hormonal therapy with tamoxifen and/or aromatase inhibitors. RESULTS In 30 months, 3,298 patients were enrolled (n = 1,649 in each arm). The major baseline characteristics were well balanced between the groups. At a median follow-up of 65 months, estimated 5-year disease-free survival rates were 79% in both groups (log-rank P = .98; hazard ratio [HR], 1.0; 95%CI, 0.86 to 1.16), and 5-year overall survival rates for both arms were 88% and 89%, respectively (log-rank P = .37; HR, 0.91; 95% CI, 0.75 to 1.11). TAC was associated with more febrile neutropenia and thrombocytopenia, and AC>T was associated with more sensory neuropathy, nail changes, and myalgia. The incidence of neutropenic infection was similar in both groups. CONCLUSION The sequential and combination regimens incorporating three drugs were equally effective but differed in toxicity profile.

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol™, Bristol-Myers Squibb and docetaxel, Taxotere™, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.

Docetaxel in the treatment of breast cancer: An update on recent studies

Recently there has been great interest in developing combination regimens involving taxanes and anthracyclines for the treatment of advanced breast cancer. Docetaxel in particular has substantial activity when combined with doxorubicin. In one randomized trial, the combination of doxorubicin 50 mg/m(2) and docetaxel 75 mg/m(2) showed significantly greater activity than doxorubicin plus cyclophosphamide (AC), producing a higher response rate (60% v 47%) and longer time to progression. In a second study, 484 patients were randomized to receive either docetaxel plus doxorubicin and cyclophosphamide (TAC) or 5-florouracil plus doxorubicin and cyclophosphamide. The response rate was significantly higher in the TAC arm (54% v 42%), including patients with unfavorable prognostic factors. Febrile neutropenia occurred more frequently in patients receiving TAC, but the incidence of infection and septic death was low and no greater than in the 5-florouracil/doxorubicin/cyclophosphamide arm. TAC was not associated with an increased risk of cardiotoxicity. Data on time to progression and survival are not yet available. The TAC and doxorubicin/docetaxel regimens have been compared with non-docetaxel-containing programs in randomized adjuvant trials which have completed accrual but are not yet mature. A second generation of adjuvant trials compares sequential versus synchronous docetaxel-based polychemotherapy. In addition, based on preclinical data suggesting a synergistic interaction between docetaxel, platinum salts, and trastuzumab, as well as preliminary data from pilot studies in patients with HER2-positive metastatic disease showing tolerability and activity, adjuvant studies of this novel three-agent combination are in progress in patients with HER2-positive early breast cancer.

Abstract S6-01: Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1

Background: Everolimus (EVE), an inhibitor of mammalian target of rapamycin (mTOR), is a protein kinase central to a number of signaling pathways regulating cell growth and proliferation. In early studies, EVE showed antitumor activity in breast cancer and synergy with both trastuzumab (TRAS) and paclitaxel. The international BOLERO-1 study is being conducted to evaluate the addition of EVE to TRAS plus paclitaxel as first-line therapy for HER2+ advanced breast cancer. Methods: In this phase 3 randomized trial, 719 adult women with HER2+ advanced breast cancer who had not received prior TRAS or chemotherapy in the advanced setting were randomized 2:1 to receive either EVE or placebo (10 mg) in combination with weekly paclitaxel and TRAS. The two primary objectives were to compare the progression-free survivals (PFS) of everolimus/trastuzumab/paclitaxel and trastuzumab/paclitaxel/placebo in both the full population and in the Hormone Receptor negative (HR-) subpopulation. Secondary endpoints included survival, response rate, and safety. The final analysis was performed after 420 PFS events were observed in the full population. Results: In the full population, the median age was 53 years, 70.4% had visceral metastases, 56.1% had ER and/or PgR +ve disease, and 43.3% had ≥ 3 metastatic sites. Previous adjuvant therapy included TRAS (11.4%) and taxane (24.7%). Conclusions: The data from the final analysis will be available in October 2014. PFS, safety, and secondary efficacy endpoints will be presented at SABCS 2014. (Funded by Novartis; BOLERO-1 ClinicalTrials.gov number, NCT00876395.) Citation Format: Sara A Hurvitz, Fabrice Andre, Zefei Jiang, Zhimin Shao, Silvia P Neciosup, Max S Mano, Ling-Min Tseng, Qingyuan Zhang, Kunwei Shen, Donggeng Liu, Lydia M Dreosti, Jifeng Feng, Howard A Burris, Masakazu Toi, Marc E Buyse, David Cabaribere, Mary-Ann Lindsay, Tiffany Kunz, Shantha Rao, Lida B Pacaud, Tetiana Taran, Dennis Slamon. Phase 3, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: BOLERO-1 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-01.