Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort
Benjamin DanielsSarah J. LordBelinda E. KielyNehmat HoussamiPhilip HaywoodChristine Y. LuRobyn L. WardSallie‐Anne Pearson
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Abstract:
Background The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2-targeted therapies in Australia. Methods/design Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2-targeted therapies to undertake this research. Ethics and dissemination Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these treatments.Keywords:
Pertuzumab
Trastuzumab emtansine
Lapatinib
HER2 overexpression occurs in about 15-20% of breast cancer cases and is associated with rapid tumor growth. The introduction in clinical practice of several drugs inhibiting the biological activity of HER2, such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1) and lapatinib, has clearly modified the prognosis for these patients. The combination of the two inhibitors of HER2, trastuzumab and pertuzumab, with a taxane (paclitaxel or docetaxel), is currently considered the first choice treatment for patients affected by HER2-positive metastatic breast cancer, whereas T-DM1 is considered the preferred treatment after the failure of first line therapy. We present the case of a 50-year-old woman affected by HER2-positive breast cancer with bone, hepatic, pulmonary and encephalic metastases, resistant both to trastuzumab-pertuzumab double-block treatment and to T-DM1, but sensitive to third line therapy to the combination lapatinib-capecitabine with a clinical response both for visceral and cerebral metastases (Oncology).
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We describe the case of a woman who has been undergoing treatment for HER2-positive metastatic breast cancer since 2002. She presented liver metastasis at diagnosis in February 2002. Combination therapy with docetaxel and trastuzumab was administered as first-line treatment, and a complete response of the hepatic lesion and a partial response at the breast primary cancer site were achieved. After 6 cycles of therapy, the patient underwent surgical excision of the breast and then received trastuzumab alone until progression, which occurred in March 2010 with the development of a right chest wall lesion. The patient progressed after therapy with trastuzumab emtansine (T-DM1) received as second-line treatment. Subsequently, a combination of lapatinib and capecitabine was started in April 2011. At this writing, the patient is still receiving treatment (24 months) and is showing a long-lasting response with a favorable safety profile.
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The overexpression of the HER2 receptor and its gene amplification are observed in c. 20% of newly diagnosed cases of breast cancer and associated with a more aggressive clinical course and poorer prognosis. New HER2-targeted drugs, such as lapatinib, pertuzumab and trastuzumab emtansine, significantly improve patient outcomes. The article reviews the role of lapatinib in HER-targeted therapy and describes the treatment sequence of two women with HER2-positive advanced breast cancer.
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Breast cancer that is characterized by amplification or overexpression of human epidermal growth factor receptor 2 (HER2) accounts for 15 to 20% of all forms of the disease. The advent of HER2-targeted drugs, such as trastuzumab, pertuzumab, lapatinib, and the antibody-drug conjugate trastuzumab emtansine, has revolutionized the treatment of both early-stage and metastatic HER2-positive breast cancer.1-4 The increasing availability of HER2-targeted agents has led to improved outcomes for patients with HER2-positive metastatic breast cancer, as reported in a study in which overall survival rose from a median of 38.7 months to 51.1 months from 2008 through 2012.5 The standard first-line . . .
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The human epidermal growth factor receptor HER2/neu gene is amplified and overexpressed in 25 to 30% of breast cancers. In women with HER2-positive advanced or metastatic breast cancer, the anti-HER2 monoclonal antibody trastuzumab and the dual tyrosine kinase inhibitor lapatinib are both established options used in combination with cytotoxic chemotherapy. In patients who progress after first-line therapy with trastuzumab plus chemotherapy, continued trastuzumab or switching to lapatinib, both in combination with cytotoxic chemotherapy, offers clinical benefit. New agents in the metastatic disease setting include pertuzumab and trastuzumab emtansine. In the first-line setting, the addition of pertuzumab to trastuzumab/docetaxel yields longer median progression-free survival than placebo plus trastuzumab/docetaxel (18.5 vs. 12.4 months; p < 0.001). In the second-line setting, trastuzumab emtansine alone improves median progression-free survival compared with capecitabine plus lapatinib (9.6 vs. 6.4 months; p < 0.0001). The combination of trastuzumab emtansine plus pertuzumab has also shown encouraging preliminary activity. Other agents in clinical development include subcutaneous trastuzumab, afatinib, and neratinib. Numerous other treatments across a range of drug classes are currently in development for the treatment of HER2-positive metastatic breast cancer.
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Metastatic breast cancer (MBC) overexpressing human epidermal growth factor receptor-2 (HER2) once had an overall worse prognosis, but therapies targeting HER2 have altered the natural course of HER2-positive disease. The initial success of trastuzumab in improving survival rates led to the clinical development of lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). HER2 protein overexpression and/or gene amplification remain the most important predictive factors for response to HER2-targeted therapies. The optimal duration of chemotherapy (CT) is at least 4–6 months (or longer) and/or to the time of maximal response, depending on toxicity and the absence of progression. HER2-targeted therapy continues until progression or unacceptable toxicity. For patients with estrogen receptor–positive/progesterone receptor–positive breast cancer who are not good candidates for CT or wish to avoid the toxicity of CT, initial hormone therapy in combination with HER2-targeted therapy is a reasonable option. For patients who relapse and were previously treated with adjuvant anti-HER2 therapy, the resumption of systemic treatment that includes HER2 blockade is recommended. As in the first-line setting, multiple choices are available for second- and third-line therapies. Successful targeting of HER2 has improved outcomes in HER2-positive breast cancer, but treatment resistance and brain metastases remain a problem. Ongoing studies are evaluating novel therapeutic approaches to overcome primary and secondary drug resistance in HER2-positive tumors.
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Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. In this article, we review clinical data informing the effective management of HER2-positive MBC.
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Abstract Breast cancer (BC) is the second most common cancer and the second leading cause of mortality among women globally. Approximately 20 to 25% of BC patients have amplification of the human epidermal growth factor receptor 2 (HER2) genes, a marker of poor prognosis. However, the introduction of anti-HER2-therapies (trastuzumab, followed closely by lapatinib, pertuzumab, trastuzumab emtansine, and neratinib) has changed the natural history of HER2-positive BC and improved the outcome in HER2-positive BC patients. The preeminence of anti-HER2 combination therapy in achieving complete inhibition of the various HER receptor dimers has been demonstrated in clinical studies. However, despite these therapeutic advances, tumors expressing estrogen receptor have poorer responses to targeted therapy and are more likely to relapse. A better understanding of resistance to existing anti-HER2 agents, along with the role played by the microenvironment and of interconnected signaling pathways, can permit tailor-made therapeutic options for each patient. This review aimed to evaluate treatment approaches for BC patients with HER2-positive disease in the adjuvant and neoadjuvant settings, also exploring the possibilities of extended duration of anti-HER2 maintenance therapy.
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Aim: To investigate the comparative effectiveness of trastuzumab emtansine (T-DM1) in a real-world population of HER2+ metastatic breast cancer (mBC) patients. Materials & methods: The Flatiron Health database was used to identify a cohort of HER2+ mBC patients who received first-line trastuzumab treatment and T-DM1 or lapatinib plus chemotherapy as second-line treatment. Overall survival was compared between the two groups. Results: A total of 278 patients with HER2+ mBC received second-line T-DM1 and 34 lapatinib plus chemotherapy. Overall survival was longer in patients treated with T-DM1 than those treated with lapatinib plus chemotherapy (adjusted hazard ratio: 0.56; 95% CI: 0.38-0.85). Conclusion: Real-world data supports the effectiveness of T-DM1 in the second-line treatment of HER2+ mBC patients.Lay abstract EMILIA was a randomized clinical trial (RCT) – a type of study designed to test whether a treatment works in a particular disease, using methods to remove possible bias. The study showed that a treatment called trastuzumab emtansine (shortened to T-DM1) improved the survival of patients with a particular type of breast cancer, known as HER2+ metastatic breast cancer (mBC). However, as clinical trials are run under controlled conditions, they do not fully reflect results under normal circumstances. In this study, we looked at the effect of treating a ‘real’ population of HER2+ mBC patients with T-DM1 in the USA. We found that T-DM1 still improved survival in these ‘real-world’ patients. Studies in the ‘real world’ can have some bias, as they are not controlled like RCTs; however, taking the results of the EMILIA RCT, along with the results of our study, supports the use of T-DM1 as a treatment option for HER2+ mBC patients.
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