Tumour heterogeneity and a long-standing paucity of effective therapies other than chemotherapy have contributed to triple-negative breast cancer (TNBC) being the subtype with the least favourable ...outcomes. In the past few years, advances in omics technologies have shed light on the relevance of the TNBC microenvironment heterogeneity, unveiling a close dynamic relationship with cancer cell features. An improved understanding of tumour-immune system co-evolution supports the need to adopt a more comprehensive view of TNBC as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody-drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease. The current therapeutic scenario is only the tip of the iceberg, as hundreds of new compounds and combinations are in development. The translation of these experimental therapies into clinical benefit is a welcome and ongoing challenge. In this Review, we describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can define different levels of risk and provide improved opportunities for tailoring treatment.
HER2-positive breast cancer Loibl, Sibylle, Prof; Gianni, Luca, MD
The Lancet (British edition),
06/2017, Letnik:
389, Številka:
10087
Journal Article
Recenzirano
Summary Anti-HER2 treatment for HER2-positive breast cancer has changed the natural biology of this disease. This Series article reviews the main achievements so far in the treatment of both ...metastatic and early HER2-positive breast cancer. The success of neoadjuvant therapy in HER2-positive early breast cancer is especially acknowledged, as pertuzumab has been approved on the basis of a higher proportion of patients achieving a pathological complete response with pertuzumab and trastuzumab than with trastuzumab alone in a neoadjuvant study. Event-free survival after the confirmatory adjuvant trial completed recruitment was numerically better with pertuzumab plus trastuzumab than with trastuzumab alone. With survival rates of almost 5 years in women with metastatic HER2-positive breast cancer and 75% of patients achieving a pathological complete response, new treatments in the past decade have clearly improved the prognosis of HER2-positive breast cancer. Despite these achievements, however, the persisting high toll of deaths resulting from HER2-positive breast cancer calls for continued, intensive clinical research of newer therapies and combinations.
Patients with metastatic triple-negative breast cancer were treated with standard chemotherapy or the anti–Trop-2 antibody–drug conjugate sacituzumab govitecan. Patients receiving the drug conjugate ...had significantly longer progression-free and overall survival as well as more frequent myelotoxic effects and diarrhea.
Summary The monoclonal antibody trastuzumab targets the growth factor receptor HER2 and has profoundly improved the course of disease and survival of women with HER2-overexpressing breast cancer. ...Because trastuzumab targets aberrant expression of HER2 in tumours addicted to HER2 activation, its clinical activity is credited largely to inhibition of intracellular signalling. A growing body of preclinical and clinical evidence shows that the immune system contributes substantially to the therapeutic effects of trastuzumab and other monoclonal antibodies in vivo. Furthermore, findings indicate that immune-related markers can provide useful predictive information and that increased clinical activity might follow activation of the immune system. Development of immunomodulatory drugs with remarkable activity in many solid tumours defines a scenario in which the combination of immune modulation with trastuzumab, or other HER2-directed drugs, will result in augmented response and clinical outcome.
Triple‐negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER‐2 genes, represents an important clinical challenge because these ...cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple‐negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple‐negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple‐negative status is sometimes used as a surrogate for basal‐like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal‐like breast cancer using ER/PR and HER‐2 negativity may provide only an approximation of the triple‐negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple‐negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple‐negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple‐negative breast cancer, again with mixed results. Agents that target poly(ADP‐ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple‐negative disease.
Triple‐negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER‐2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple‐negative breast cancer. This article will review the clinical problem of triple‐negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies.
Triple‐negative breast cancer, characterized by tumors that do not express estrogen receptor, progesterone receptor, or HER‐2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple‐negative breast cancer. However, there are a number of potential therapies currently under investigation that may eventually improve outcomes in these patients.
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies ...and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.
Summary Background Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women ...with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. Methods HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov ( NCT00045032 ). Findings Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09–11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68–0·86) and death (0·74, 0·64–0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89–1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. Interpretation 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. Funding F Hoffmann-La Roche (Roche).
This Review outlines the understanding and management of triple-negative breast cancer (TNBC). TNBC shares morphological and genetic abnormalities with basal-like breast cancer (BLBC), a subgroup of ...breast cancer defined by gene-expression profiling. However, TNBC and BLBC tumors are heterogeneous and overlap is incomplete. Breast cancers found in BRCA1 mutation carriers are also frequently triple negative and basal like. TNBC and BLBC occur most frequently in young women, especially African Americans, and tend to exhibit aggressive, metastatic behavior. These tumors respond to conventional chemotherapy but relapse more frequently than hormone receptor-positive, luminal subtypes and have a worse prognosis. New systemic therapies are urgently needed as most patients with TNBC and/or BLBC relapse with distant metastases, and hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in patients with TNBC and/or BRCA1-associated tumors. Increased understanding of the genetic abnormalities involved in the pathogenesis of TNBC, BLBC and BRCA1-associated tumors is opening up new therapeutic possibilities for these hard-to-treat breast cancers.
Summary Background The antibody–drug conjugate trastuzumab emtansine is indicated for the treatment of patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a ...taxane. Approval of this drug was based on progression-free survival and interim overall survival data from the phase 3 EMILIA study. In this report, we present a descriptive analysis of the final overall survival data from that trial. Methods EMILIA was a randomised, international, open-label, phase 3 study of men and women aged 18 years or older with HER2-positive unresectable, locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane. Enrolled patients were randomly assigned (1:1) via a hierarchical, dynamic randomisation scheme and an interactive voice response system to trastuzumab emtansine (3·6 mg/kg intravenously every 3 weeks) or control (capecitabine 1000 mg/m2 self-administered orally twice daily on days 1–14 on each 21-day cycle, plus lapatinib 1250 mg orally once daily on days 1–21). Randomisation was stratified by world region (USA vs western Europe vs or other), number of previous chemotherapy regimens for unresectable, locally advanced, or metastatic disease (0 or 1 vs >1), and disease involvement (visceral vs non-visceral). The coprimary efficacy endpoints were progression-free survival (per independent review committee assessment) and overall survival. Efficacy was analysed in the intention-to-treat population; safety was analysed in all patients who received at least one dose of study treatment, with patients analysed according to the treatment actually received. On May 30, 2012, the study protocol was amended to allow crossover from control to trastuzumab emtansine after the second interim overall survival analysis crossed the prespecified overall survival efficacy boundary. This study is registered with ClinicalTrials.gov , number NCT00829166. Findings Between Feb 23, 2009, and Oct 13, 2011, 991 eligible patients were enrolled and randomly assigned to either trastuzumab emtansine (n=495) or capecitabine and lapatinib (control; n=496). In this final descriptive analysis, median overall survival was longer with trastuzumab emtansine than with control (29·9 months 95% CI 26·3–34·1 vs 25·9 months 95% CI 22·7–28·3; hazard ratio 0·75 95% CI 0·64–0·88). 136 (27%) of 496 patients crossed over from control to trastuzumab emtansine after the second interim overall survival analysis (median follow-up duration 24·1 months IQR 19·5–26·1). Of those patients originally randomly assigned to trastuzumab emtansine, 254 (51%) of 495 received capecitabine and 241 49% of 495 received lapatinib (separately or in combination) after study drug discontinuation. In the safety population (488 patients treated with capecitabine plus lapatinib, 490 patients treated with trastuzumab emtansine), fewer grade 3 or worse adverse events occurred with trastuzumab emtansine (233 48% of 490) than with capecitabine plus lapatinib control treatment (291 60% of 488). In the control group, the most frequently reported grade 3 or worse adverse events were diarrhoea (103 21% of 488 patients) followed by palmar–plantar erythrodysaesthesia syndrome (87 18%), and vomiting (24 5%). The safety profile of trastuzumab emtansine was similar to that reported previously; the most frequently reported grade 3 or worse adverse events in the trastuzumab emtansine group were thrombocytopenia (70 14% of 490), increased aspartate aminotransferase levels (22 5%), and anaemia (19 4%). Nine patients died from adverse events; five of these deaths were judged to be related to treatment (two in the control group coronary artery disease and multiorgan failure and three in the trastuzumab emtansine group metabolic encephalopathy, neutropenic sepsis, and acute myeloid leukaemia). Interpretation This descriptive analysis of final overall survival in the EMILIA trial shows that trastuzumab emtansine improved overall survival in patients with previously treated HER2-positive metastatic breast cancer even in the presence of crossover treatment. The safety profile was similar to that reported in previous analyses, reaffirming trastuzumab emtansine as an efficacious and tolerable treatment in this patient population. Funding F Hoffmann-La Roche/Genentech.
Women with metastatic breast cancer that had progressed during treatment with trastuzumab plus a taxane were assigned to lapatinib plus capecitabine or to trastuzumab emtansine. The response rate and ...survival were significantly better with trastuzumab emtansine.
Amplification of human epidermal growth factor receptor 2 (HER2, also called ErbB2) occurs in approximately 20% of breast cancers and is associated with shortened survival.
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Combining HER2-targeted agents with standard chemotherapy is an effective therapeutic approach for patients with HER2-positive metastatic breast cancer. When combined with first-line chemotherapy, trastuzumab increases the time to progression and overall survival among patients with metastatic disease.
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The addition of lapatinib to capecitabine increases the time to progression in patients previously treated with trastuzumab, an anthracycline, and a taxane,
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and this combination is a standard option for disease progression with trastuzumab.
Trastuzumab emtansine . . .
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