Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast
Clinical Trial Service Unit (CTSU), Richard Doll Bldg, Old Road Campus, University of Oxford, Oxford OX3 7LF, United Kingdom. . JNCI Monographs
Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ (DCIS). A total of 3729 women were eligible for analysis. Radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event (ie, either recurrent DCIS or invasive cancer) by 15.2% (SE 1.6%, 12.9% vs 28.1% 2 P <.00001), and it was effective regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size. The proportional reduction in ipsilateral breast events was greater in older than in younger women (2P < .0004 for difference between proportional reductions; 10-year absolute risks: 18.5% vs 29.1% at ages <50 years, 10.8% vs 27.8% at ages ≥ 50 years) but did not differ significantly according to any other available factor. Even for women with negative margins and small low-grade tumors, the absolute reduction in the 10-year risk of ipsilateral breast events was 18.0% (SE 5.5, 12.1% vs 30.1%, 2P = .002). After 10 years of follow-up, there was, however, no significant effect on breast cancer mortality, mortality from causes other than breast cancer, or all-cause mortality.
Available from: Seema Khan
- "OS followed similar trends with the greatest advantage for high grade lesions (HR 0.4, 95% CI 0.3e0.6). The authors suggest a prospective trial to test the value of surgery for low-grade DCIS, but the small number of low grade lesions in this retrospective (albeit population-based) analysis is of concern, and existing data regarding the risk of subsequent invasive recurrence, even among women with low grade lesions that were excised but not radiated, are cause for concern  . 3. Anastrozole versus tamoxifen for hormone receptor positive DCIS  A long awaited clinical trial, NSABP B-35 addressed the benefit of anastrozole versus tamoxifen in postmenopausal patients with DCIS , hoping to improve upon the reduction in invasive and non-invasive recurrences, and contralateral primaries that follows use of adjuvant tamoxifen. "
Available from: Mary Kathryn Pitner
- "Radiotherapy is one of the cornerstones in the treatment of patients with breast cancer [7,8]. Radiation greatly reduces the risk of recurrence in women with ductal carcinoma in situ[9,10] and in breast cancer patients who are lymph node positive [11-13]. The outcomes following chemotherapy vary depending on the subtype: for example, ER-PR-HER2- and ER-PR-HER2+ breast cancers respond better than luminal subtypes to anthracycline-based chemotherapies . "
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ABSTRACT: The discovery of molecular markers associated with various breast cancer subtypes has greatly improved the treatment and outcome of breast cancer patients. Unfortunately, breast cancer cells acquire resistance to various therapies. Mounting evidence suggests that resistance is rooted in the deregulation of the G1 phase regulatory machinery.
To address whether deregulation of the G1 phase regulatory machinery contributes to radiotherapy resistance, the MCF10A immortalized human mammary epithelial cell line, ER-PR-Her2+ and ER-PR-Her2- breast cancer cell lines were irradiated. Colony formation assays measured radioresistance, while immunocytochemistry, Western blots, and flow cytometry measured the cell cycle, DNA replication, mitosis, apoptosis, and DNA breaks.
Molecular markers common to all cell lines were overexpressed, including cyclin A1 and cyclin D1, which impinge on CDK2 and CDK4 activities, respectively. We addressed their potential role in radioresistance by generating cell lines stably expressing small hairpin RNAs (shRNA) against CDK2 and CDK4. None of the cell lines knocked down for CDK2 displayed radiosensitization. In contrast, all cell lines knocked down for CDK4 were significantly radiosensitized, and a CDK4/CDK6 inhibitor sensitized MDA-MB-468 to radiation induced apoptosis. Our data showed that silencing CDK4 significantly increases radiation induced cell apoptosis in cell lines without significantly altering cell cycle progression, or DNA repair after irradiation. Our results indicate lower levels of phospho-Bad at ser136 upon CDK4 silencing and ionizing radiation, which has been shown to signal apoptosis.
Based on our data we conclude that knockdown of CDK4 activity sensitizes breast cancer cells to radiation by activating apoptosis pathways.
Available from: Aliana Guerrieri-Gonzaga
- "Four randomised clinical trials have shown that RT after BCS reduced the risk of local recurrence (whether in situ or invasive) by approximately 50% at 10 and 15 years of follow-up (Fisher et al, 1998; Bijker et al, 2006; Cuzick et al, 2011; Wapnir et al, 2011). In a meta-analysis of 3729 women with DIN, RT after BCS reduced the absolute 10-year risk of any ipsilateral breast event by 15.2% (12.9% with RT vs 28.1% without RT; P<0.001) (Correa et al, 2010). Similarly, randomised clinical trials have shown that adding adjuvant tamoxifen reduces the risk of all breast cancer events (ipsilateral plus contralateral) by approximately 30% at 10 and 15 years of follow-up (Cuzick et al, 2011; Wapnir et al, 2011; Allred et al, 2012). "
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The post-surgical management of ductal intraepithelial neoplasia (DIN) of the breast is still a dilemma. Ki-67 labelling index (LI) has been proposed as an independent predictive and prognostic factor in early breast cancer.
The prognostic and predictive roles of Ki-67 LI were evaluated with a multivariable Cox regression model in a cohort of 1171 consecutive patients operated for DIN in a single institution from 1997 to 2007.
Radiotherapy (RT) was protective in subjects with DIN with Ki-67 LI ≥14%, whereas no evidence of benefit was seen for Ki-67 LI <14%, irrespective of nuclear grade and presence of necrosis. Notably, the higher the Ki-67 LI, the stronger the effect of RT (P-interaction <0.01). Hormonal therapy (HT) was effective in both Luminal A (adjusted hazard ratio (HR)=0.56 (95% CI, 0.33–0.97)) and Luminal B/Her2neg DIN (HR 0.51 (95% CI, 0.27–0.95)).
Our data suggest that Ki-67 LI may be a useful prognostic and predictive adjunct in DIN patients. The Ki-67 LI of 14% could be a potential cutoff for better categorising this population of women at increased risk for breast cancer and in which adjuvant treatment (RT, HT) should be differently addressed, independent of histological grade and presence of necrosis.
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