Tailoring treatment for ductal intraepithelial neoplasia of the breast according to Ki-67 and molecular phenotype

FULL PAPER British Journal of Cancer (2013) 108, 1593–1601 | doi: 10.1038/bjc.2013.147 Keywords: ductal intraepithelial neoplasia; DCIS; Ki-67; prognosis; radiotherapy; low-dose tamoxifen Tailoring treatment for ductal intraepithelial neoplasia of the breast according to Ki-67 and molecular phenotype M Lazzeroni*,1,8, A Guerrieri-Gonzaga1,8, E Botteri2, M C Leonardi3, N Rotmensz2, D Serrano1, C Varricchio1, D Disalvatore2, A Del Castillo4, F Bassi4, G Pagani4, A DeCensi1,5, G Viale6,7, B Bonanni1 and G Pruneri6,7 1 Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy; 2Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy; 3Division of Radiotherapy, Department of Medical Imaging and Radiation Sciences, European Institute of Oncology, Milan, Italy; 4Division of Senology, European Institute of Oncology, Milan, Italy; 5Division of Medical Oncology, EO Ospedali Galliera, Genoa, Italy; 6Division of Pathology, Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy and 7University of Milan, School of Medicine, Milan, Italy Background: 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. Methods: 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. Results: Radiotherapy (RT) was protective in subjects with DIN with Ki-67 LI Z14%, whereas no evidence of benefit was seen for Ki-67 LI o14%, irrespective of nuclear grade and presence of necrosis. Notably, the higher the Ki-67 LI, the stronger the effect of RT (P-interaction o0.01). Hormonal therapy (HT) was effective in both Luminal A (adjusted hazard ratio (HR) ¼ 0.56 (95% CI, 0.33–0.97)) and Luminal B/Her2neg DIN (HR 0.51 (95% CI, 0.27–0.95)). Conclusion: 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. The post-surgical management of patients with ductal carcinoma in situ of the breast, recently referred to as ductal intraepithelial neoplasia (DIN1c, 2 and 3; Veronesi et al, 2006) is still a dilemma (Solin, 2012). Following a diagnosis of DIN, the risk of ipsilateral recurrence after breast-conserving surgery (BCS) without radiation therapy (RT) or hormonal therapy (HT) is approximately 30% at 10 years (Bijker et al, 2006). 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; Po0.001) (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). However, neither RT nor HT have been reported to improve survival, and this is particularly relevant when considering that both RT and HT carry rare but serious risks (Paszat et al, 1998, 2007; Cuzick et al, 2011; Wapnir et al, 2011; Allred et al, 2012). *Correspondence: Dr M Lazzeroni; E-mail: 8 These two authors contributed equally to this work. Received 5 December 2012; revised 1 March 2013; accepted 7 March 2013; published online 11 April 2013 & 2013 Cancer Research UK. All rights reserved 0007 – 0920/13 www.bjcancer.com | DOI:10.1038/bjc.2013.147 1593 BRITISH JOURNAL OF CANCER As ipsilateral mastectomy is a dearly prize to pay for a minimal or absent risk of recurrence, patients and physicians often opt for conservative surgery followed by RT and HT to reduce the risk of recurrence, despite awareness that this may be an over-treatment for most patients. To improve clinical decision making, Rudloff et al (2010) reported an internally validated nomogram integrating 10 clinical, pathological and treatment-related variables to predict the risk of local recurrence for DIN patients. Unfortunately, a recent report on independent series of patients by Yi et al (2012) did not fully validate this nomogram and again the debate about how to manage at best DIN patients has been re-opened. Both studies (Rudloff et al, 2010; Yi et al, 2012) concur that molecular profiling will potentially improve risk stratification for women with DIN. Gene expression studies recently led to a better understanding of the biological complexity of invasive breast carcinomas (BCs), allowing to discriminate different molecular subtypes (Luminal A (LumA), Luminal B (LumB), human epidermal growth factor receptor-2 (HER2)-enriched and basal-like) with specific clinical behaviour, whose progression may be tackled using different therapeutic strategies. Interestingly, the application of traditional immunohistochemical markers such as oestrogen receptor (ER), progesterone receptor (PgR), HER2 status and Ki-67 labelling index (LI) has been convincingly demonstrated to be a robust surrogate for the molecular assays in BC classification, and has been therefore recommended in clinical practice and recently endorsed by the San Gallen panellists (Goldhirsch et al, 2011). In particular, Ki-67 LI has been proposed as an independent predictive and prognostic factor in early BC (Urruticoechea et al, 2005), although uncertainty concerning the most effective threshold for discriminating between low and highly proliferative tumours still persists. To assess the predictive and prognostic power of immunohistochemically defined molecular subtypes and of Ki-67 LI in DIN, we selected a large retrospective series of consecutive patients treated in a single institution over a time frame of 410 years. PATIENTS AND METHODS Study population. The study cohort consisted of all consecutive women included in a dedicated institutional database who underwent primary breast surgery at the European Institute of Oncology (EIO) between 1 January 1997 and 31 December 2007, who were diagnosed with DIN1c-3, and who were followed-up by the EIO staff. This is a retrospective study reported in accordance with the REMARK criteria (McShane et al, 2006). Relevant data on patients’ medical history, kind of surgery and pathologic assessment of morphologic and biologic features were combined. Treatment assignment. Tre (...truncated)