| Name: | Description: | Size: | Format: | |
|---|---|---|---|---|
| 4.93 MB | Adobe PDF |
Authors
Advisor(s)
Abstract(s)
O tratamento hormonal adjuvante de doentes com carcinoma da mama melhora a sobrevivência global. O uso em contexto de mundo real, efetividade, tolerabilidade e adesão a inovações recentes da terapia hormonal adjuvante de cancro da mama não está bem caracterizado. Para abordar estes pontos e assim apoiar a tomada de decisão de doentes-médicos e a investigação clínica futura desenvolvemos uma série de projetos com o propósito de: 1) descrever a implementação na prática clínica de mundo real de inovações recentes no campo da terapia hormonal adjuvante de cancro da mama e sumarizar a sua efetividade, 2) quantificar o impacto da terapia hormonal adjuvante na qualidade de vida das doentes e 3) quantificar a adesão e persistência das doentes à terapia hormonal adjuvante. Para concluir estas tarefas utilizámos diferentes estudos de coorte e aplicámos métodos padrão e inovadores de análise de dados.
Fazendo recurso de duas coortes retrospetivas derivadas do Registo Oncológico Regional do Sul, a primeira com ~1300 mulheres pós-menopáusicas e a segunda com ~1700 mulheres pré-menopáusicas, identificámos que quer os inibidores da aromatase (IA) quer a supressão da função ovárica (SFO) foram introduzidos com sucesso na prática clínica após publicações científicas de referência em 2005 e 2014, respetivamente. Na coorte pós-menopáusica, 41% das doentes receberam um IA (16% em monoterapia e 25% em sequência) e 59% tamoxifeno com diferenças por centro. Após um acompanhamento mediano de 6.3 anos, os IA associaram-se a melhor sobrevivência global (SG) quando comparados com tamoxifeno (HR-ajustado 0.5, IC 95% 0.37-0.81). Fazendo recurso complementar de uma coorte retrospetiva estado-unidense de ~800 mulheres pós-menopáusicas com tumores lobulares, registámos resultados semelhantes e não foi identificada heterogeneidade de eficácia por tipo histológico, em específico quando comparando carcinomas lobulares puros a carcinomas ductais e lobulares mistos. Na coorte pré-menopáusica, 17% das doentes foram tratadas com SFO com um crescimento substancial do uso de 2014 em diante (16% vs. 25% após 2014), particularmente para a combinação com IA (0.4% vs. 8% após 2014). Após um acompanhamento mediano de ~3 anos, doentes tratadas com SFO tiveram melhor SG que doentes não tratadas com SFO (HR-ajustado 0.44, IC 95% 0.19-0.96). Fazendo recurso de uma sub-coorte de ~4300 doentes com cancro da mama com resultados reportados por doente (patient reported outcomes) disponíveis do estudo CANTO, uma coorte prospetiva francesa, descrevemos um impacto substancial do tratamento na qualidade de vida (QdV) 2 anos após o diagnóstico. Usando o C30 summary score da EORTC, um resultado compósito de várias funções e sintomas, a terapia hormonal, mas não a quimioterapia, teve um impacto persistente na QdV 2 anos após o diagnóstico com diferenças nos domínios impactados. Adicionalmente, expusemos um efeito diferencial do tratamento por estado menopausico: em doentes pré-menopáusicas a quimioterapia parece ser o promotor principal da deterioração de domínios de QdV, enquanto que em doentes pós-menopáusicas foi a terapia hormonal o promotor principal da deterioração da QdV. Finalmente, fazendo recurso de uma segunda sub-coorte de ~1200 derivada do estudo CANTO e de doentes que estavam a tomar tamoxifeno e com avaliação sérica do tamoxifeno, identificámos que 1 em cada 6 mulheres (16%) eram não-aderentes ao tratamento, i.e. tinham os valores séricos de tamoxifeno abaixo da linha de corte de adesão. Esta proporção foi maior que aquela auto-reportada (12.3%). Após um acompanhamento mediano de 2 anos após a avaliação do tamoxifeno sérico, doentes não aderentes quando avaliadas por via bioquímica tiveram uma sobrevivência livre de recidiva à distância mais curta (HR-ajustado de 2.31, IC 95% 1.05-5.06).
Este trabalho detalhou a cinética de introdução na prática clínica de inovações recentes na terapia hormonal adjuvante. Adicionalmente, revelou evidência de mundo real da efetividade de IA e SFO adjuvantes. Estes dados sugeriram porém que para uma proporção substancial de doentes a terapia hormonal leva a um impacto persistente e negativo na QdV, especialmente em mulheres pós-menopáusicas, tal como a uma proporção alarmante de não-adesão ao tratamento, até certo ponto relacionada com questões de tolerabilidade.
Adjuvant endocrine therapy leads to substantial gains in breast cancer survival outcomes. The real-world use, effectiveness, tolerability and adherence to recent innovations in the field of adjuvant endocrine therapy for breast cancer is not well characterized. To tackle these concerns and hence help patient-physician decision making and future clinical research we developed a series of projects aiming to: 1) describe the implementation in real-world practice of recent innovations in the field of adjuvant endocrine therapy for breast cancer and summarize its effectiveness, 2) quantify adjuvant endocrine therapy impact on patients’ quality of life and 3) quantify patients adherence and persistence to adjuvant endocrine therapy. To do this, we used different cohort studies and applied standard and novel statistical methods. Using two retrospective cohorts from Southern Portugal Cancer Registry, one of ~1300 postmenopausal women and the other of ~1700 premenopausal women, we identified that both aromatase inhibitors (AI) and ovarian function suppression (OFS) were successfully introduced in clinical practice after landmark publication in 2005 and 2014, respectively. In the postmenopausal cohort, 41% of patients received an AI (16% as monotherapy, 25% as sequential therapy) and 59% tamoxifen with differences by center. After a median follow-up of 6.3 years, AI use was associated with a better overall survival (OS) when compared with tamoxifen (adjusted-HR 0.55, 95% CI 0.37-0.81). Using a complementary retrospective US cohort of ~800 postmenopausal women with lobular tumors, similar findings were registered and no heterogeneity in efficacy was recorded by histology, in specific comparing pure lobular carcinomas to mixed ductal and lobular carcinomas. In the premenopausal cohort, 17% of patients were treated with OFS with a substantial increase of its use from 2014 onward (16% vs. 25% after 2014), particularly for the combination with AI (0.4% vs. 8% after 2014). After a median follow-up of ~3 years, patients treated with OFS had a better OS than those not treated with OFS (adjusted-HR 0.44, 95% CI 0.19-0.96). Using a sub-cohort of ~4300 breast cancer patients with available patient reported outcomes from CANTO, a nationwide French prospective cohort, we described a substantial impact of treatment on QoL 2 years after diagnosis. Using the EORTC C30 summary score, a composite score of several functions and symptoms, endocrine therapy but not chemotherapy had a persistent impact on QoL 2 years after diagnosis with differences by specific domains. In addition, we uncovered a differential effect of treatment by menopausal status: in premenopausal patients CT seems to be the predominant driver of QoL domains deterioration, whereas in postmenopausal patients it was ET the predominant driver of QoL deterioration. Finally, using a second sub-cohort of ~1200 patients from CANTO that were taking adjuvant tamoxifen and with serum assessment of tamoxifen, we identified that 1 in every 6 women (16%) were non-adherent, i.e. had serum tamoxifen levels were below the adherence threshold. This proportion was higher than the self-reported rate of non-adherence (12.3%). After a median follow-up time of 2 years from tamoxifen serum assessment, biochemically defined non-adherent patients had a shorter DDFS (adjusted-HR of 2.31, 95% CI 1.05-5.06). This work detailed the kinetics of introduction in clinical practice of recent adjuvant endocrine treatment innovations. In addition, it provides real-world evidence of the effectiveness of adjuvant AIs and OFS. Nevertheless, it suggests that for a substantial number of patients endocrine therapy leads to a persistent negative impact on QoL, especially in postmenopausal women, and to an alarming proportion of non-adherence to treatment, to a certain extent related to tolerability issues.
Adjuvant endocrine therapy leads to substantial gains in breast cancer survival outcomes. The real-world use, effectiveness, tolerability and adherence to recent innovations in the field of adjuvant endocrine therapy for breast cancer is not well characterized. To tackle these concerns and hence help patient-physician decision making and future clinical research we developed a series of projects aiming to: 1) describe the implementation in real-world practice of recent innovations in the field of adjuvant endocrine therapy for breast cancer and summarize its effectiveness, 2) quantify adjuvant endocrine therapy impact on patients’ quality of life and 3) quantify patients adherence and persistence to adjuvant endocrine therapy. To do this, we used different cohort studies and applied standard and novel statistical methods. Using two retrospective cohorts from Southern Portugal Cancer Registry, one of ~1300 postmenopausal women and the other of ~1700 premenopausal women, we identified that both aromatase inhibitors (AI) and ovarian function suppression (OFS) were successfully introduced in clinical practice after landmark publication in 2005 and 2014, respectively. In the postmenopausal cohort, 41% of patients received an AI (16% as monotherapy, 25% as sequential therapy) and 59% tamoxifen with differences by center. After a median follow-up of 6.3 years, AI use was associated with a better overall survival (OS) when compared with tamoxifen (adjusted-HR 0.55, 95% CI 0.37-0.81). Using a complementary retrospective US cohort of ~800 postmenopausal women with lobular tumors, similar findings were registered and no heterogeneity in efficacy was recorded by histology, in specific comparing pure lobular carcinomas to mixed ductal and lobular carcinomas. In the premenopausal cohort, 17% of patients were treated with OFS with a substantial increase of its use from 2014 onward (16% vs. 25% after 2014), particularly for the combination with AI (0.4% vs. 8% after 2014). After a median follow-up of ~3 years, patients treated with OFS had a better OS than those not treated with OFS (adjusted-HR 0.44, 95% CI 0.19-0.96). Using a sub-cohort of ~4300 breast cancer patients with available patient reported outcomes from CANTO, a nationwide French prospective cohort, we described a substantial impact of treatment on QoL 2 years after diagnosis. Using the EORTC C30 summary score, a composite score of several functions and symptoms, endocrine therapy but not chemotherapy had a persistent impact on QoL 2 years after diagnosis with differences by specific domains. In addition, we uncovered a differential effect of treatment by menopausal status: in premenopausal patients CT seems to be the predominant driver of QoL domains deterioration, whereas in postmenopausal patients it was ET the predominant driver of QoL deterioration. Finally, using a second sub-cohort of ~1200 patients from CANTO that were taking adjuvant tamoxifen and with serum assessment of tamoxifen, we identified that 1 in every 6 women (16%) were non-adherent, i.e. had serum tamoxifen levels were below the adherence threshold. This proportion was higher than the self-reported rate of non-adherence (12.3%). After a median follow-up time of 2 years from tamoxifen serum assessment, biochemically defined non-adherent patients had a shorter DDFS (adjusted-HR of 2.31, 95% CI 1.05-5.06). This work detailed the kinetics of introduction in clinical practice of recent adjuvant endocrine treatment innovations. In addition, it provides real-world evidence of the effectiveness of adjuvant AIs and OFS. Nevertheless, it suggests that for a substantial number of patients endocrine therapy leads to a persistent negative impact on QoL, especially in postmenopausal women, and to an alarming proportion of non-adherence to treatment, to a certain extent related to tolerability issues.
Description
Keywords
Cancro de mama precoce Tratamentos adjuvantes Hormonoterapia Efetividade terapêutica Qualidade de vida Adesão ao tratamento Teses de doutoramento - 2020