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Introduction: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described. Methods: Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy. Results: Disease-free survival (DFS) was 75% after 5 and 61% after 10 years, respectively. Patients with HER2+ hormone receptor-positive (HR+ (hormone receptor-positive); ER+ (estrogen receptor-positive) or PR+ (progesterone receptor-positive)) disease had a significantly better DFS than patients with HER2+ HR- (ER-/PR-) disease (hazard ratio 0.72, P = 0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2+ HR- compared to HER2+ HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients (hazard ratio 0.59, P = 0.002 for years 1 to 5). The high early risk of recurrence of HER2+ HR- patients declined sharply over time, so that it was similar to that seen in HER2+ HR+ patients in years 6 to 10 (hazard ratio 0.97, P = 0.92 for years 6 to 10). Conclusions: Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+ HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2+ HRearly BC should be prioritized for consideration of adjuvant anti-HER2 therapy. [ABSTRACT FROM AUTHOR]

Summary: Background: Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab—the standard adjuvant treatment. We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis. Methods: This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 33 centres with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00374322. Findings: Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4–60·0) in the lapatinib group and 48·3 (0·7–61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70–1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67–1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3–4 diarrhoea (97 [6%] vs nine [<1%]), rash (72 [5%] vs three [<1%]), and hepatobiliary disorders (36 [2%] vs one [<1%]). Interpretation: Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population. However, exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival. Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or cannot receive adjuvant trastuzumab. Funding: GlaxoSmithKline. [Copyright &y& Elsevier]

Abstract: Background and Methods: The optimal treatment of locally advanced breast cancer (LABC) remains undetermined. We analyzed factors influencing local therapy in LABC in a pooled material including three large clinical series. Results: Of a total of 787 patients, local therapy was given in 604, surgery in 184, radiotherapy in 69, and a combination thereof in 351. The use of local therapy was related to younger age, lower clinical T and N stage, no skin involvement and no progression during induction chemotherapy. The use of surgery was related to younger age, lower clinical T and N stage, no clinical skin involvement and response to induction chemotherapy. The use of postoperative radiotherapy was correlated with larger tumor size, higher number of positive lymph nodes, positive surgical margin, extracapsular lymph node extension, lymphatic vessel invasion and skin involvement. Conclusions: The most frequent local therapy in LABC remains a combination of surgery and radiotherapy. Clinical and pathological characteristics influence the type of local treatment. [Copyright &y& Elsevier]

Summary: Trastuzumab has revolutionised the treatment of HER2-positive early-stage breast cancer and is now standard of care in combination with chemotherapy for patients with tumours larger than 1 cm. However, 5 years after publication of the landmark trials establishing the efficacy of the drug, the management of small (≤1 cm), HER2-positive tumours remains difficult. Most small breast cancers have a good prognosis and adjuvant chemotherapy is not routinely recommended. However, retrospective data suggest that some small HER2-positive cancers might have a worse clinical outcome than others. This notion raises the key clinical question of whether patients with small HER2-positive cancers should be offered adjuvant trastuzumab and chemotherapy. The pivotal adjuvant trastuzumab trials did not include patients with tumours smaller than 1 cm, but a subset analysis of one trial showed that patients with tumours 1–2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort. Clinicians face the dilemma of whether the potential reduction in risk of recurrence in this patient group warrants the toxic effects and risks of adjuvant chemotherapy and trastuzumab. In this review, we discuss the evidence for prognosis of small HER2-positive cancers, and for possible benefit from adjuvant trastuzumab. We suggest potential treatment strategies and clinical trial designs to address this important issue. On the basis of present evidence, we recommend that the benefits and risks of adjuvant trastuzumab should be discussed with patients with small, HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Letrozole, a third generation aromatase inhibitor, has been compared with tamoxifen in the treatment of advanced breast cancer and as neoadjuvant therapy. In a first-line trial in advanced disease, 939 post menopausal women were randomised double blind to receive treatment with letrozole 2.5 mg daily or tamoxifen 20 mg daily. Letrozole was significantly superior in terms of median time to progression (9.4 months versus 6.1 months, P = 0.0001), objective response (30% versus 20%, P = 0.0006), and clinical benefit (49% versus 38%, P = 0.0001). Superiority of letrozole was independent of disease site, receptor status, or prior adjuvant anti-oestrogen therapy. In an extended phase of this trial, 200 patients were crossed over to tamoxifen after letrozole, compared with 197 crossed over to letrozole after tamoxifen. Median overall survival was 34 months for letrozole versus 30 months for tamoxifen (not significant).In a similar randomised double-blind neoadjuvant trial, 337 post menopausal patients with large ER/or PgR positive T2–T4 cancers, either requiring mastectomy or locally advanced, were randomised to preoperative letrozole or tamoxifen for 4 months prior to surgery. Overall response was 55% for letrozole versus 36% for tamoxifen (P < 0.001). Conservative surgery was possible in 45% of patients treated with letrozole versus 35% with tamoxifen (P = 0.022).In both trials, both treatments were well tolerated with no significant differences in side effects.These results indicate that letrozole is more active than tamoxifen both as neoadjuvant therapy and as first-line treatment in advanced disease. They support the importance of current adjuvant trials comparing the two treatments. [Copyright &y& Elsevier]

Responses by Trevor J. Powles, Sue Ashley, Ian E. Smith, and Mitch Dowsett to a letter to the editor about the article on tamoxifen, breast cancer, and hormone replacement therapy in the previous issue are presented.

The article discusses chemotherapy regimens for breast cancer in the United Kingdom. Adjuvant chemotherapy trials include NEAT, TACT, and CALGB 9741. Chemotherapy and tamoxifen are effective in women with high risk estrogen receptor positive cancer. Adjuvant treatment for patients with operable breast cancer includes endocrine treatment and chemotherapy. Trastuzumab is used in patients whose breast cancers overexpress HER2 and improves survival in patients with metastatic disease when used in combination with paclitaxel and docetaxel. Bisphosphonate treatment is used to reduce bone loss.

Examines the efficacy of the combination treatment of tamoxifen and aminoglutethimide in advanced breast cancer. Comparison of drugs as single agents; Use of the standard criteria for staging disease and for defining objective response; Disadvantages of the combined endocrine treatment.

The article discusses the combined use of signal transduction inhibitors (STIs) and endocrine therapies to enhance endocrine responsiveness and delay acquired resistance in the treatment of breast cancer. According to the author, many biological agents have been developed to target key proteins along the HER-2 and mitogen-activated protein kinases (MAPK) signal transduction cascades but their clinical trials have been unsuccessful.

Presents a letter to the editor to comment on the article by D. Mauri et al. entitled "Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis".

Abstract: Considerable heterogeneity exists amongst oestrogen receptor positive (ER+ve) breast cancer in both its molecular profile and response to therapy. Attempts to better define variation amongst breast tumours have led to the definition of four main “intrinsic” subtypes of breast cancer with two of these classes, Luminal A and B, composed almost entirely of ER+ve cancers. In this study we set out to investigate the significance of intrinsic subtypes within a group of ER+ve breast cancers treated with neoadjuvant anastrozole. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with anastrozole was analyzed on Illumina 48K microarrays. Gene-expression based subtypes and risk of relapse (ROR) scores for tumours pre- and post-treatment were determined using the PAM50 method. Amongst pre-treatment samples, all intrinsic subtypes were found to be present, although luminal groups were represented most highly. Luminal A and B tumours obtained similar benefit from treatment, as measured by the proportional fall in the proliferation marker Ki67 upon treatment (mean suppression=75.5% vs 75.7%). Tumours classified as basal and Her2-like showed poor reductions in Ki67 upon treatment. Residual Ki67 staining after two weeks remained higher in the Luminal B group. ROR score was significantly associated with anti-proliferative response to AI and with clinical response. These results suggest that in the short-term, Luminal A and B tumours may gain similar benefit from an AI but that the higher residual Ki67 level seen in Luminal B is indicative of poorer long term outcome. [Copyright &y& Elsevier]