RESUMEN
INTRODUCTION: Estrogen receptor-α (ER) and human epidermal growth factor receptor 2 (HER2) positivity are inversely correlated by standard criteria. However, we investigated the quantitative relation between ER and HER2 expression at both RNA and protein levels in HER2+ve and HER2-ve breast carcinomas. METHODS: ER and HER2 levels were assessed with immunohistochemistry (IHC) and (for HER2) fluorescent in situ hybridization (FISH) and by quantitative reverse transcription-polymerase chain reaction (q-RT-PCR) in formalin-fixed primary breast cancers from 448 patients in the National Cancer Research Institute (NCRI) Adjuvant Breast Cancer Trial (ABC) tamoxifen-only arm. Relations at the RNA level were assessed in 1,139 TransATAC tumors. RESULTS: ER and HER2 RNA levels were negatively correlated as expected in HER2+ve (IHC 3+ and/or FISH-amplified) tumors (r = -0.45; P = 0.0028). However, in HER2-ve tumors (ER+ve and ER-ve combined), a significant positive correlation was found (r = 0.43; P < 0.0001), HER2 RNA levels being 1.74-fold higher in ER+ve versus ER-ve tumors. This correlation was maintained in the ER+veHER2-ve subgroup (r = 0.24; P = 0.0023) and confirmed in this subgroup in 1,139 TransATAC tumours (r = 0.25; P < 0.0001). The positive relation extended to IHC-detected ER in ABC: mean ± 95% confidence interval (CI) H-scores were 90 ± 19 and 134 ± 19 for 0 and 1+ HER2 IHC categories, respectively (P = 0.0013). A trend toward lower relapse-free survival (RFS) was observed in patients with the lowest levels of ER and HER2 RNA levels within the ER+veHER2-ve subgroup both for ABC and TransATAC cohorts. CONCLUSIONS: ER and HER2 expression is positively correlated in HER2-ve tumors. The distinction between HER2+ve and HER2-ve is greater in ER-ve than in ER+ve tumors. These findings are important to consider in clinical trials of anti-HER2 and anti-endocrine therapy in HER2-ve disease. TRIAL REGISTRATION: Clinical trial identifier: ISRCTN31514446.
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Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Valor Predictivo de las Pruebas , Pronóstico , Receptores de Estrógenos/genética , Tamoxifeno/uso terapéuticoRESUMEN
BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. METHODS: We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3-6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. FINDINGS: 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5-61·3), six (4·3%; 95% CI 1·6-9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2-8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2-5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5-6·2) of 138 men, three (2·2%; 0·5-6·3) of 137, and none (0·0%; 97·5% CI 0·0-2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. INTERPRETATION: Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. FUNDING: Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.
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Fraccionamiento de la Dosis de Radiación , Neoplasias de la Próstata/radioterapia , Radioterapia de Intensidad Modulada , Anciano , Anciano de 80 o más Años , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Traumatismos por Radiación/etiología , Radioterapia de Intensidad Modulada/efectos adversos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Reino UnidoRESUMEN
PURPOSE: The justification for partial breast radiotherapy after breast conservation surgery assumes that ipsilateral breast tumor relapses (IBTR) outside the index quadrant are mostly new primary (NP) tumors that develop despite radiotherapy. We tested the hypothesis that whole-breast radiotherapy (WBRT) is ineffective in preventing NP by comparing development rates in irradiated and contralateral breasts after tumor excision and WBRT. METHODS AND MATERIALS: We retrospectively reviewed 1,410 women with breast cancer who were entered into a prospective randomized trial of radiotherapy fractionation and monitored annually for ipsilateral breast tumor relapses (IBTR) and contralateral breast cancer (CLBC). Cases of IBTR were classified into local recurrence (LR) or NP tumors based on location and histology and were subdivided as definite or likely depending on clinical data. Rates of ipsilateral NP and CLBC were compared over a 15-year period of follow-up. RESULTS: At a median follow-up of 10.1 years, there were 150 documented cases of IBTR: 118 (79%) cases were definite or likely LR; 27 (18%) cases were definite or likely NP; and 5 (3%) cases could not be classified. There were 71 cases of CLBC. The crude proportion of definite-plus-likely NP was 1.9% (27/1,410) patients compared with 5% (71/1,410) CLBC patients. Cumulative incidence rates at 5, 10, and 15 years were 0.8%, 2.0%, and 3.5%, respectively, for definite-plus-likely NP and 2.4%, 5.8%, and 7.9%, respectively for CLBC, suggesting a difference in the rates of NP and CLBC. CONCLUSIONS: This analysis suggests that WBRT reduces the rate of ipsilateral NP tumors. The late presentation of NP has implications for the reporting of trials that are testing partial breast radiotherapy.
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Neoplasias de la Mama/prevención & control , Neoplasias de la Mama/radioterapia , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Primarias Secundarias/prevención & control , Adulto , Anciano , Mama/patología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Mastectomía Segmentaria , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/patología , Tamaño de los Órganos , Dosificación Radioterapéutica , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Few trials of adjuvant breast radiotherapy have incorporated patient-reported breast symptoms and related areas of quality of life. We assessed these measures in a quality-of-life study that was part of the randomised START (Standardisation of Breast Radiotherapy) trials. METHODS: In START trial A, 2236 patients were randomly assigned to receive either 39 Gy or 41.6 Gy delivered in 13 fractions over 5 weeks or a global standard of 50 Gy in 25 fractions. In START trial B, 2215 women were randomly assigned to receive either 40 Gy in 15 fractions over 3 weeks or the same control regimen (50 Gy in 25 fractions) as in trial A. 2739 patients were eligible for the quality-of-life study of whom 2208 (81%) were accrued (1129 patients from trial A and 1079 from trial B). Participants completed the EORTC QLQ-C30 and BR23 questionnaires and protocol-specific radiotherapy items up to 5 years after radiotherapy. We compared results across regimens with generalised estimating equations and survival analyses. The START trials are registered, ISRCTN59368779. FINDINGS: At 5 years, up to 40% women reported moderate or marked changes to the breast after radiotherapy, and arm and shoulder pain affected up to a third of patients. Breast symptoms and body image concerns reduced over time. Rates of radiotherapy adverse effects were lower for the 39 Gy regimen in trial A and the 40 Gy regimen in trial B, compared with the 50 Gy control regimen; rates of radiotherapy adverse effects were similar between the 41.6 Gy and 50 Gy regimens in trial A. Adverse change in skin appearance was significantly lower for patients who received 39 Gy compared with those who received 50 Gy (HR 0.63, 95% CI 0.47-0.84) and for those who received 40 Gy compared with those who received 50 Gy (0.76, 0.60-0.97); no significant difference was observed between patients who received 41.6 Gy and those who received 50 Gy in trial A (0.83, 0.63-1.08). Patient self-ratings of breast symptoms discriminated a 10% difference in randomised dose intensity. Up to a third of women reported moderate or marked pain in the arm and shoulder over 5 years whilst more than 10% experienced moderate or marked arm and hand swelling, with no significant difference in arm/shoulder subscale scores between the regimens in trial A or trial B; many baseline arm and shoulder symptoms were associated with prior surgery. INTERPRETATION: A substantial proportion of women report moderate or marked breast, arm, and shoulder symptoms over 5 years of follow-up after radiotherapy, but with no detriment to body image. Nonetheless, most patients stand to gain from hypofractionated radiotherapy regimens with a potential for fewer adverse effects; this strengthens the evidence from the START trials for hypofractionated regimens for women requiring radiotherapy for early breast cancer. FUNDING: Cancer Research UK, UK Medical Research Council, UK Department of Health.
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Imagen Corporal , Neoplasias de la Mama/radioterapia , Calidad de Vida , Traumatismos por Radiación/epidemiología , Piel/efectos de la radiación , Brazo/efectos de la radiación , Mama/efectos de la radiación , Neoplasias de la Mama/psicología , Neoplasias de la Mama/cirugía , Relación Dosis-Respuesta en la Radiación , Femenino , Estudios de Seguimiento , Humanos , Mastectomía Radical , Mastectomía Segmentaria , Persona de Mediana Edad , Dosis de Radiación , Traumatismos por Radiación/psicología , Radioterapia/efectos adversos , Radioterapia/métodos , Radioterapia Adyuvante/efectos adversos , Hombro/efectos de la radiación , Análisis de Supervivencia , Reino Unido/epidemiologíaRESUMEN
Prospective data are limited on the course of anxiety and depression and their determinants in women with early breast cancer. These parameters were assessed before adjuvant radiotherapy (RT) and over 5 years follow-up. Of 2208 women recruited to the START QOL study, 35% reported clinically relevant levels of anxiety and/or depression pre-RT; there was no significant change in these proportions over time. However, 75% women with high baseline anxiety recorded further high scores over time whilst one in six had high scores at every follow-up point. Depression showed a similar pattern with lower frequencies at all time points; very few with initial normal scores developed clinically relevant anxiety or depression over time. Lower educational level predicted worse anxiety and depression over time; younger age predicted worse anxiety and chemotherapy predicted worse depression. Scores in the borderline or case range for anxiety or depression at baseline were both significantly associated with worse mood states over 5 years. These findings indicate the course of anxiety and depression in women with specific risk factors. This subgroup of patients requires greater clinical attention.
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Ansiedad/epidemiología , Neoplasias de la Mama/psicología , Depresión/epidemiología , Calidad de Vida , Radioterapia Adyuvante/psicología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/radioterapia , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Reino UnidoRESUMEN
Quality of life (QOL) assessments of women entering a UK randomised trial of adjuvant radiotherapy (START) were investigated to estimate the independent effects on QOL of age, time since surgery, type of breast surgery, chemotherapy and endocrine therapy. QOL was evaluated using the EORTC general cancer QOL scale (EORTC QLQ-C30), breast cancer module (BR23), the Body Image Scale (BIS) and the Hospital Anxiety and Depression Scale (HADS). Independent effects of age and clinical factors were tested using multiple regression analysis. A total of 2208 (mean age 56.9 years, range 26-87) consented to the QOL study prior to radiotherapy; 17.1% had undergone mastectomy (Mx) and the remainder had undergone a wide local excision (WLE). 33.3% had received adjuvant chemotherapy (CT) and 56.7% were taking endocrine therapy (ET). Age had significant effects on QOL with older and younger subgroups predicting poorer QOL for different domains. CT affected most QOL domains and resulted in worse body image, sexual functioning, breast and arm symptoms (<0.001). Mx was associated with greater body image concerns (p<0.001), and WLE with more arm symptoms (p=0.01). There were no effects of ET on QOL. Women <50 years (proxy pre-menopausal) had worse QOL in respect of anxiety, body image and breast symptoms but age and clinical factors had no effect on depression. Overall, QOL and mental health were favourable for most women about to start RT, but younger age and receiving CT were significant risk factors for poorer QOL, and so patients in these subgroups warrant further monitoring. Surgery had a limited impact and ET had no effect on QOL.