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Risk prediction for local versus regional/metastatic tumors after initial ductal carcinoma in situ diagnosis treated by lumpectomy.

ABSTRACT: Among women diagnosed with ductal carcinoma in situ (DCIS), we identified factors associated with local invasive cancer (LIC) and regional/metastatic invasive cancer (RMIC) and provide 10-year risks based on clinically relevant factors. We created a retrospective, population-based cohort of 1492 women with an initial diagnosis of DCIS (1983-1996) treated by lumpectomy alone. Histological and molecular markers (Ki67, ER, PR, COX-2, p16, ERBB2) were collected on DCIS cases with a subsequent tumor (DCIS, LIC, or RMIC) and a subsample of frequency-matched controls without subsequent tumors. Competing risks methods were used to identify factors associated with LIC and RMIC and cumulative incidence methods to estimate 10-year risks for combinations of factors. Median follow-up time was 12.6 years (range 0.5-29.5 years). The overall 10-year risk of LIC (11.9 %) was higher than for RMIC (3.8 %). About half of women with initial DCIS lesions are detected by mammography and p16 negative and have a 10-year risk of LIC of 6.2 % (95 % CI 5.8-6.8 %) and RMIC of 1.2 % (95 % CI 1.1-1.3 %). Premenopausal women whose DCIS lesion was p16 positive or p16 negative and detected by palpation had high 10-year risk of LIC of 23.0 % (95 % CI 19.3-27.4 %). Ten-year risk of RMIC was highest at 22.5 % (95 % CI 13.8-48.1 %) for those positive for p16, COX-2, and ERRB2, and negative for ER, but prevalence of this group is low at 3 %. Ten-year risk of LIC and RMIC is low for the majority diagnosed with DCIS. Combinations of molecular markers and method of detection of initial DCIS lesion can differentiate women at low and high risk of LIC and RMIC.

SUBMITTER: Molinaro AM

PROVIDER: S-EPMC6805143 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Risk prediction for local versus regional/metastatic tumors after initial ductal carcinoma in situ diagnosis treated by lumpectomy.

Molinaro Annette M AM Sison Jennette D JD Ljung Britt-Marie BM Tlsty Thea D TD Kerlikowske Karla K

Breast cancer research and treatment 20160504 2

Among women diagnosed with ductal carcinoma in situ (DCIS), we identified factors associated with local invasive cancer (LIC) and regional/metastatic invasive cancer (RMIC) and provide 10-year risks based on clinically relevant factors. We created a retrospective, population-based cohort of 1492 women with an initial diagnosis of DCIS (1983-1996) treated by lumpectomy alone. Histological and molecular markers (Ki67, ER, PR, COX-2, p16, ERBB2) were collected on DCIS cases with a subsequent tumor ...[more]

PMID: 27146587

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Project description:BackgroundStudies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.MethodsWe conducted a nested case-control study in a population-based cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. We collected clinical characteristics and information on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk.ResultsFactors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16(+)COX-2(+)Ki67(+)) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were detected by mammography and were p16, COX-2, and Ki67 triple negative (p16(-)COX-2(-)Ki67(-)) (4.1%, 95% CI = 3.4% to 5.0%). In a multivariable model, DCIS lesions that were p16(+)COX-2(+)Ki67(+) or those detected by palpation were statistically significantly associated with subsequent invasive cancer, but nuclear grade was not. Eight-year risk of subsequent DCIS was highest for women with DCIS lesions that had disease-free margins of 1 mm or greater combined with either ER(-)ERBB2(+)Ki67(+) or p16(+)COX-2(-)Ki67(+) status (23.6%, 95% CI = 18.1% to 34.0%).ConclusionBiomarkers can identify which women who were initially diagnosed with DCIS are at high or low risk of subsequent invasive cancer, whereas histopathology information cannot.

Project description:ImportancePatients with ductal carcinoma in situ (DCIS) are treated with radiotherapy to reduce their risk of local invasive recurrence after breast-conserving surgery. However, the association of radiotherapy with breast cancer survival in patients with DCIS has not yet been clearly established.ObjectiveTo determine the extent to which radiotherapy is associated with reduced risk of breast cancer mortality in a large cohort of patients treated for DCIS, using a propensity score-based matching approach.Design, setting, and participantsThis cohort study of women who had first primary DCIS diagnosed between 1998 and 2014 used data from the Surveillance, Epidemiology, and End Results 18 registries database. Information on age and year of diagnosis, ethnicity, income, tumor size, tumor grade, estrogen receptor status, all treatments (surgery and radiation), and outcomes (invasive local recurrence and death from breast cancer) was abstracted for 140 366 women diagnosed with first primary DCIS. Three separate comparisons were performed using 1:1 matching: lumpectomy with radiation vs lumpectomy alone; lumpectomy alone vs mastectomy; and lumpectomy with radiation vs mastectomy.ExposuresUse of radiotherapy and/or extent of surgery.Main outcomes and measuresCrude and adjusted 15-year breast cancer-specific mortality.ResultsOf the 140 366 patients with DCIS in the cohort (109 712 [78.2%] white; mean [SD] age, 58.8 [12.3] years), 35 070 (25.0%) were treated with lumpectomy alone, 65 301 (46.5%) were treated with lumpectomy and radiotherapy, and 39 995 (28.5%) were treated with mastectomy. The actuarial 15-year breast cancer mortality rate was 2.33% for patients treated with lumpectomy alone, 1.74% for patients treated with lumpectomy and radiation, and 2.26% for patients treated with mastectomy. The adjusted hazard ratios for death were 0.77 (95% CI, 0.67-0.88) for lumpectomy and radiotherapy vs lumpectomy alone (29 465 propensity-matched pairs), 0.91 (95% CI, 0.78-1.05) for mastectomy alone vs lumpectomy alone (20 832 propensity-matched pairs), and 0.75 (95% CI, 0.65-0.87) for lumpectomy and radiotherapy vs mastectomy (29 865 propensity-matched pairs).Conclusions and relevanceIn patients with DCIS, treatment with lumpectomy and radiotherapy was associated with a significant reduction in breast cancer mortality compared with either lumpectomy alone or mastectomy alone. This suggests that the survival benefit of radiation is likely not due to local control, but rather to systemic effects.

Project description:The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms.The study was done at 333 hospitals in North America. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were randomly assigned to receive either tamoxifen (20 mg/day) or anastrazole (1 mg/day) for 5 years, stratified by age (<60 years vs ?60 years). Patients and investigators were masked to treatment allocation. Patients completed questionnaires at baseline and every 6 months thereafter for 6 years. The primary outcomes were SF-12 physical and mental health component scale scores, and vasomotor symptoms (as per the BCPT symptom scale). Secondary outcomes were vaginal symptoms and sexual functioning. Exploratory outcomes were musculoskeletal pain, bladder symptoms, gynaecological symptoms, cognitive symptoms, weight problems, vitality, and depression. We did the analyses by intention to treat, including patients who completed questionnaires at baseline and at least once during follow-up. This study is registered with ClinicalTrials.gov, NCT00053898.Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled in the study, of whom 1193 were included in the quality-of-life substudy: 601 assigned to tamoxifen and 592 assigned to anastrozole. We detected no significant difference between treatment groups for: physical health scores (mean severity score 46·72 for tamoxifen vs 45·85 for anastrozole; p=0·20), mental health scores (52·38 vs 51·48; p=0·38), energy and fatigue (58·34 vs 57·54; p=0·86), or symptoms of depression (6·19 vs 6·39; p=0·46) over 5 years. Vasomotor symptoms (1·33 vs 1·17; p=0·011), difficulty with bladder control (0·96 vs 0·80; p=0·0002), and gynaecological symptoms (0·29 vs 0·18; p<0·0001) were significantly more severe in the tamoxifen group than in the anastrozole group. Musculoskeletal pain (1·50 vs 1·72; p=0·0006) and vaginal symptoms (0·76 vs 0·86; p=0·035) were significantly worse in the anastrozole group than in the tamoxifen group. Sexual functioning did not differ significantly between the two treatments (43·65 vs 45·29; p=0·56). Younger age was significantly associated with more severe vasomotor symptoms (mean severity score 1·45 for age <60 years vs 0·65 for age ?60 years; p=0·0006), vaginal symptoms (0·98 vs 0·65; p<0·0001), weight problems (1·32 vs 1·02; p<0·0001), and gynaecological symptoms (0·26 vs 0·22; p=0·014).Given the similar efficacy of tamoxifen and anastrozole for women older than age 60 years, decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug. For women younger than 60 years old, treatment decisions might be driven by efficacy (favouring anastrozole); however, if the side-effects of anastrozole are intolerable, then switching to tamoxifen is a good alternative.US National Cancer Institute, AstraZeneca Pharmaceuticals.

Project description:Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy.The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ?60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00053898, and is complete.Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group.Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ.US National Cancer Institute and AstraZeneca Pharmaceuticals LP.

Dataset Information

Risk prediction for local versus regional/metastatic tumors after initial ductal carcinoma in situ diagnosis treated by lumpectomy.

Publications

Risk prediction for local versus regional/metastatic tumors after initial ductal carcinoma in situ diagnosis treated by lumpectomy.

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