• Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study.

      Colleoni, Marco; Giobbie-Hurder, Anita; Regan, Meredith M; Thürlimann, Beat; Mouridsen, Henning; Mauriac, Louis; Forbes, John F; Paridaens, Robert; Láng, István; Smith, Ian; et al. (2011-03-20)
      Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy.
    • Overcoming endocrine resistance in breast cancer: are signal transduction inhibitors the answer?

      Bedard, Philippe L; Freedman, Orit C; Howell, Anthony; Clemons, Mark; Division of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada. (2008-04)
      Endocrine therapy is probably the most important systemic therapy for hormone receptor positive breast cancer. Hormonal manipulation was the first targeted treatment employed in breast cancer therapy even before the role of the estrogen (ER) and progesterone receptors (PR) had been elucidated. Unfortunately, a substantial proportion of patients, despite being ER and/or PR positive, are either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Signaling through complex growth factor receptor pathways, which activate the ER are emerging as important causes of endocrine resistance. Targeted therapies, such as signal transduction inhibitors (STIs), are being explored as agents to be able to potentially overcome this crosstalk and thus, resistance to hormone treatment. This article reviews the biology of the ER, the proposed mechanisms of endocrine resistance, and ongoing clinical trials with STIs in combination with hormonal manipulation as a means to overcome endocrine resistance.
    • Predictive algorithms for adjuvant therapy: TransATAC.

      Dowsett, Mitch; Salter, Janine; Zabaglo, Lila; Mallon, Elizabeth A; Howell, Anthony; Buzdar, Aman; Forbes, John F; Pineda, S; Cuzick, Jack; Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road, London SW36JJ, UK. (2011-07)
      Estrogen receptor (ER) positive primary breast cancers have a wide range of clinical outcomes. Prediction of the likely course of the disease aids treatment decision-making. In the translational arm of the ATAC (anastrozole or tamoxifen alone or combined) trial (TransATAC) we have assessed individual and multiparameter biomarkers for their prediction of overall and distant recurrence. None of the biomarkers identified differential benefit for anastrozole versus tamoxifen. Each of ER, PgR, HER2 and Ki67 was associated with risk of recurrence. A combination of these to create a single predictor IHC4 was as informative as the 21-gene recurrence score (RS). Integration of each of these molecular profiles with classical clinicopathologic variables provided the most accurate prediction of outcome.
    • Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer.

      Cuzick, J; Dowsett, M; Pineda, S; Wale, C; Salter, J; Quinn, E; Zabaglo, L; Mallon, E; Green, A R; Ellis, I O; et al. (2011-11-10)
      We recently reported that the mRNA-based, 21-gene Genomic Health recurrence score (GHI-RS) provided additional prognostic information regarding distant recurrence beyond that obtained from classical clinicopathologic factors (age, nodal status, tumor size, grade, endocrine treatment) in women with early breast cancer, confirming earlier reports. The aim of this article is to determine how much of this information is contained in standard immunohistochemical (IHC) markers.
    • Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial.

      Ellis, Paul A; Barrett-Lee, P J; Johnson, Lindsay; Cameron, David; Wardley, Andrew M; O'Reilly, Susan; Verrill, Mark W; Smith, Ian; Yarnold, John; Coleman, Robert E; et al. (2009-05-16)
      BACKGROUND: Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. METHODS: In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. FINDINGS: All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). INTERPRETATION: This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. FUNDING: Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.
    • Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study.

      Kaufman, Bella; Mackey, John R; Clemens, Michael R; Bapsy, Poonamalle P; Vaid, Ashok; Wardley, Andrew M; Tjulandin, Sergei; Jahn, Michaela; Lehle, Michaela; Feyereislova, Andrea; et al. (2009-11-20)
      PURPOSE: TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure. CONCLUSION: Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.