https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61121-X.pdf

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

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Microenvironmental regulation of tumor progression and metastasis.

Purpose To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker. Methods The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations. Results Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy. Recommendations The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly...

/pdf/american-society-of-clinical-oncology-college-of-american-5b47o39c65.pdf

American society of clinical oncology/college of american pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer

Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011

A b s t r ac t The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. Conclusions Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2- positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa064320

Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer

Background A number of phase III studies have shown significant progression-free survival (PFS) benefits with the combination of bevacizumab (Bev) and either first-line capecitabine (X) or taxane therapy in LR/MBC. The ongoing open-label, randomized, phase III CECOG-sponsored TURANDOT study (CECOG/BC.1.3.005) is investigating the efficacy and safety of first-line Bev plus paclitaxel (P) versus Bev plus X in this setting. Materials and methods: Eligible patients (pts) are aged ≥18 years with HER2−negative, chemonaive LR/MBC, an ECOG performance status of 0–2 and a life expectancy >12 weeks. Prior chemotherapy and concomitant hormonal therapy for LR/MBC are not permitted, but prior (neo)adjuvant chemotherapy is allowed if completed ≥6 months before randomization or ≥12 months if taxane based. Pts are randomized to receive Bev 10mg/kg days 1, 15 plus P 90mg/m2 days 1, 8, 15, q28d (Arm A) or Bev 15mg/kg day 1 plus X 1,000mg/m2 bid days 1–14, q21d (Arm B) until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is to demonstrate non-inferiority in overall survival (OS) with Bev plus P versus Bev plus X (upper limit ≤1.33 for the two-sided confidence interval for hazard ratio [HR]). Secondary objectives are: comparison of overall response rate (RECIST criteria); PFS; time to response; duration of response; time to treatment failure; safety (CTCAE version 3); and quality of life (EORTC QLQ-30). The recruitment target is 560 pts. A sample size of 490 pts in the per-protocol population will be required to provide 80% power to reject the null hypothesis of inferiority at a one-sided significance level of 0.025, assuming a 24-month median OS with Bev plus P and an alternative hypothesis of HR=1. Data cut-off for adverse event reports was 12 Apr 2010. Interim and final efficacy analyses will be triggered after 175 and 389 events, respectively. Results: Recruitment to the study began in Sep 2008 and was completed in Aug 2010, with 561 pts randomized. Follow-up is ongoing. Conclusions: TURANDOT is the first study to examine the efficacy and safety of Bev plus P versus Bev plus X as first-line treatment for pts with LR/MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-01-02.

OT2-01-02: First-Line Bevacizumab in Combination with Capecitabine or Paclitaxel for HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): A Randomized Phase III Trial.

Summary With the development of various targeted therapies in breast cancer, detection of biomarkers for predicting treatment efficacy gains importance. With the definition of intrinsic subtypes, breast cancer has paved the way for personalized treatment. Already known and recently recognized targets play an important role both in metastatic and early breast cancer. As a result, early molecular profiling is becoming a part of early diagnostic work-up. Notwithstanding, further treatment targets and agents are needed, particularly in the most aggressive subtype encompassing heterogenous diseases under the group of triple negative breast cancer. 

/pdf/molecular-profiling-leading-to-personalized-treatment-in-3i20ovt9.pdf

Molecular profiling leading to personalized treatment in breast cancer

BACKGROUND Brain metastases (BM) are frequently diagnosed in patients (pts) with Her2-positive metastatic breast cancer (BC); a rising incidence was also reported in triple-negative disease. We hypothesized that pts with triple-negative or Her2-positive tumours had shorter BMFS as compared to other BC subtypes. Therefore, we aimed to compare BMFS in pts with Her2-positive, estrogen receptor (ER) positive and triple-negative BC treated at the Medical University of Vienna from 1999–2009. In Her2-positive tumours, we further investigated the influence of ER co-expression on BMFS, as Her2-positive / ER-positive tumours were reported to express less aggressive biological properties. METHODS BMFS was defined as primary study endpoint and measured as the interval from diagnosis of metastatic BC until diagnosis of BM. A total of 168 pts were identified from a breast cancer database. 34 pts were excluded from this analysis as brain was the first site of disease progression; hence complete datasets from 134 pts were available (69 Her2-positive; 33 triple-negative; 32 ER-positive). Her2 status was analyzed by immunohistochemistry (IHC) and reanalyzed by FISH if a score of 2+ was gained. ER was analyzed by IHC; ER negative tumours were defined by a cut-off value of RESULTS Median BMFS in triple-negative pts was 14 months (m) (95% CI 12.17−15.83), as compared to 25 m (95% CI 13.37−36.62) in Her2-positive (p=0.001) and 35 m (95% CI 19.79−50.22) in ER-positive pts (p In Her2-positive pts, prior trastuzumab treatment for metastatic disease prolonged median BMFS (29 vs. 11 m; p ER-expression (HR 2.03; 95%CI 1.22−3.36; p CONCLUSIONS BMFS in triple-negative disease is significantly shorter as compared to Her2-positive or ER-positive tumours, mirroring the aggressiveness of this breast cancer subtype. Probably due to improved systemic disease control, trastuzumab significantly prolonged BMFS in Her2-positive pts. Longer BMFS in ER/Her2 co-positive disease reflects a less aggressive subtype of Her2-positive breast cancer which is less likely to benefit from strategies of BM screening or prevention. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-05.

Günther G. Steger

Papers

OT2-01-02: First-Line Bevacizumab in Combination with Capecitabine or Paclitaxel for HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): A Randomized Phase III Trial.

Molecular profiling leading to personalized treatment in breast cancer

P4-17-05: Brain Metastasis Free Survival (BMFS) Differs between Breast Cancer Subtypes.

5061 POSTER Impact of Systemic Anti-Her2 Treatment on Overall Survival in Patients With Brain Metastases From Her2-overexpressing Breast Cancer

microRNA expression profiles distinguish colorectal cancer patients in two regions of Austria.