Y. De Rycke

Second malignancies after breast cancer: the impact of different treatment modalities.

Treatment for non-metastatic breast cancer (BC) may be the cause of second malignancies in long-term survivors. Our aim was to investigate whether survivors present a higher risk of malignancy than the general population according to treatment received. We analysed data for 16 705 BC survivors treated at the Curie Institute (1981–1997) by either chemotherapy (various regimens), radiotherapy (high-energy photons from a 60Co unit or linear accelerator) and/or hormone therapy (2–5 years of tamoxifen). We calculated age-standardized incidence ratios (SIRs) for each malignancy, using data for the general French population from five regional registries. At a median follow-up 10.5 years, 709 patients had developed a second malignancy. The greatest increases in risk were for leukaemia (SIR: 2.07 (1.52–2.75)), ovarian cancer (SIR: 1.6 (1.27–2.04)) and gynaecological (cervical/endometrial) cancer (SIR: 1.6 (1.34–1.89); P<0.0001). The SIR for gastrointestinal cancer, the most common malignancy, was 0.82 (0.70–0.95; P<0.007). The increase in leukaemia was most strongly related to chemotherapy and that in gynaecological cancers to hormone therapy. Radiotherapy alone also had a significant, although lesser, effect on leukaemia and gynaecological cancer incidence. The increased risk of sarcomas and lung cancer was attributed to radiotherapy. No increased risk was observed for malignant melanoma, lymphoma, genitourinary, thyroid or head and neck cancer. There is a significantly increased risk of several kinds of second malignancy in women treated for BC, compared with the general population. This increase may be related to adjuvant treatment in some cases. However, the absolute risk is small.

Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group

Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1–2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal MYCN, 1 died of complications and 16 relapsed, 2 of whom died; 5-year relapse-free survival (RFS) and overall survival (OS) rates were 94.3% (95% confidence interval (CI): 91.6–97) and 98.9% (95% CI: 97.7–100), respectively. Of the 123 stage 2 patients with normal MYCN, 1 died of sepsis and 22 relapsed, 8 of whom died (RFS 82.8%, 95% CI: 76.2–89.5; OS 93.2%, 95% CI: 88.7–97.8). In stage 2, OS and RFS were worse for patients with elevated LDH and unfavourable histopathology. Of 16 children with MYCNA, 7 were stage 1 (5 relapses and 4 deaths) and 9 were stage 2 (3 relapses and 2 deaths) patients. In conclusion, surgery alone yielded excellent OS for both stage 1 and 2 neuroblastoma without MYCNA, although stage 2 patients with unfavourable histopathology and elevated LDH suffered a high number of relapses. Both stage 1 and 2 patients with MYCNA were at greater risk of relapse.

Male pattern baldness and the risk of prostate cancer

BACKGROUND Androgens play a role in the development of both androgenic alopecia, commonly known as male pattern baldness, and prostate cancer. We set out to study if early-onset androgenic alopecia was associated with an increased risk of prostate cancer later in life. PATIENTS AND METHODS A total of 669 subjects (388 with a history of prostate cancer and 281 without) were enrolled in this study. All subjects were asked to score their balding pattern at ages 20, 30 and 40. Statistical comparison was subsequently done between both groups of patients. RESULTS Our study revealed that patients with prostate cancer were twice as likely to have androgenic alopecia at age 20 [odds ratio (OR) 2.01, P = 0.0285]. The pattern of hair loss was not a predictive factor for the development of cancer. There was no association between early-onset alopecia and an earlier diagnosis of prostate cancer or with the development of more aggressive tumors. CONCLUSIONS This study shows an association between early-onset androgenic alopecia and the development of prostate cancer. Whether this population can benefit from routine prostate cancer screening or systematic use of 5-alpha reductase inhibitors as primary prevention remains to be determined.

Disseminated tumor cells and the risk of locoregional recurrence in nonmetastatic breast cancer

BACKGROUND In early breast cancer patients, bone marrow (BM)-disseminated tumor cells (DTCs) were associated with distant metastasis and locoregional recurrence. Our aim was to determine whether BM DTC detection could be related to specific locoregional dissemination of cancer cells, according to radiotherapy volumes. PATIENTS AND METHODS The relationship between locoregional recurrence-free survival (LRFS) and DTC detection was evaluated according to the various locoregional volumes irradiated after surgery. RESULTS BM DTCs were detected in 94 of 621 stage I-III breast cancer patients (15%) and were not associated with axillary node status. Eighteen patients (2.9%) experienced locoregional recurrence (median follow-up 56 months), of whom eight (44%) were initially BM DTC positive. BM DTC detection was the only prognostic factor for LRFS [P = 0.0005, odds ratio = 5.2 (2.0-13.1), multivariate analysis]. In BM DTC-positive patients, a longer LRFS was observed in those who were given adjuvant hormone therapy (P = 0.03) and radiotherapy to supraclavicular nodes (SCNs)/internal mammary nodes (IMNs) (P = 0.055) (multivariate analysis; interaction test: P = 0.028). CONCLUSIONS The presence of DTC in BM may be associated with a different pattern of locoregional cancer cell dissemination and influences LRFS. The possible reseeding of the primary cancer area by DTC could be prevented by systemic hormone therapy but also by SCN/IMN irradiation.

Association with pregnancy increases the risk of local recurrence but does not impact overall survival in breast cancer: A case–control study of 87 cases

Pregnancy-associated breast cancer (PABC) constitutes 7% of all BCs in young women. The prognosis of PABC remains controversial. In this study, we evaluated the impact of the association of pregnancy with BC on the rates of overall survival (OS), disease free survival (DFS), and distant and local recurrence-free survival. We conducted a retrospective unicenter case-control study. We enrolled PABC patients treated at our institution between 1992 and 2009. For each case, 2 BC controls were matched for age and year of diagnosis. Univariate and multivariate analyses were performed to assess the parameters associated with prognosis. Eighty-seven PABC patients were enrolled and matched with 174 controls. The univariate analysis did not reveal any significant differences in OS, DFS or distant recurrence rates between the 2 groups. Pregnancy associated status, a tumor larger than T2 and neoadjuvant chemotherapy as the primary treatment were significantly associated with an increased risk of local relapse. The multivariate analysis showed that the pregnancy associated status and the tumor size were strong prognostic factors of local recurrence. Pregnancy associated status negates the prognostic value of tumor size, as both T0-T2 and T3-T4 PABC patients have the same poor prognosis as control BC patients with T3-T4 tumors. Interestingly, although PABC patients have more locally advanced tumors, they did not have a higher rate of radical surgery than the control BC patients. Pregnancy associated status is a strong prognostic factor of local relapse in BC. In PABC patients, when possible, radical surgery should be the preferred first treatment step.

Validation over time of a nomogram including HER2 status to predict the sentinel node positivity in early breast carcinoma

BACKGROUND The molecular subtypes of breast cancer have different axillary status. A nomogram including the interaction covariate between estrogen receptor (ER) and HER2 has been recently published (Reyal et al. PLOS One, May 2011) and allows to identify the patients with a high risk of positive sentinel lymph node (SLN). The purpose of our study was to validate this model on an independent population. METHODS We studied 755 consecutive patients treated at Institut Curie for operable breast cancer with sentinel node biopsies in 2009. The multivariate model, including age, tumor size, lymphovascular invasion and interaction covariate between ER and HER2 status, was used to calculate the theoretical risk of positive sentinel lymph node (SLN) for all patients. The performance of the model on our population was then evaluated in terms of discrimination (area under the curve AUC) and of calibration (Hosmer-Lemeshow HL test). RESULTS our population was significantly different from the training population for the following variables: median tumor size in mm, lymphovascular invasion, positive ER and age. The nomogram showed similar results in our population than in the training population in terms of discrimination (AUC=0.72 [0.68-0.76] versus 0.73 [0.7-0.75] and calibration (HL p=0.4 versus p=0.35). CONCLUSIONS Despite significant differences between the two populations concerning variables which are part of the nomogram, the model was validated in our population. This nomogram is robust over time to predict the likelihood of positive SLN according to molecular subtypes defined by surrogate markers ER and HER2 determined by immunohistochemistry in clinical practice.

Distant Metastasis Free Survival (DMFS) in Breast Cancer Patients with Micrometastases (pN1mi) in the Sentinel Lymph Node (SLN): Results in 582 Positive-SLN Patients in a Single Institution.

Background:The risk of developing distant metastases (DM) in pN1mi and isolated tumor cells (pN0i+) patients remains under question. Does occult axillary node metastases is an additional factor for using an adjuvant systemic therapy (AST) in early breast cancer ?Patients and Methods:Among 2695 patients operated on from 2000 to 2006 for SLN, 582 patients had a positive SNB: 307 were pN1, 154 pN1mi and 121 pN0i+ (6th AJCC-classification). All patients underwent an immediate or delayed Axillary Lymph Node Dissection (ALND). We report the results for DMFS [median follow-up of 56 months (2-105)].We used Kaplan-Meier method and Cox regression for multivariate analysis.Results:ALND were positive in pN1, pN1mi and pN0i+ patients respectively in 127 (41,3%), 20 (13%) and 14 (11.6%) of these patients. On univariate and multivariate analysis, positive ALND, mitotic index, pathologic tumor size were significantly related to the DMFS; on multivariate analysis, the type of axillary lymph node metastases was an additional significative factor. There was not relationship between pN0i+ and the development of DM. Surprisingly, patients with pN1mi had a 2.8 higher risk for developing DM than pN1 patients. pN1 patients receive more AST than pN1mi (75% and 22%), however AST was not prognostic (p=0.49).Conclusion:In our series, patients with pN1mi were associated with a worse prognosis related to DMFS compared to pN1. Use of AST and/or biological primary tumor characteristics could explain this paradoxical result. Longer follow-up and larger series are needed to determine the prognostic significance of axillary occult metastases. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 308.

357PDDETERMINANTS OF CENTRAL NERVOUS SYSTEM (CNS) METASTASES IN A COHORT OF 620 EARLY BREAST CANCER PATIENTS AFTER 11 YEARS FOLLOW UP: ROLE OF DISSEMINATED TUMOR CELL (DTC) IN BONE MARROW (BM) DETECTED AT PRIMARY DIAGNOSIS

ABSTRACT Aim: BM DTC detection is known to be a prognostic factor for distant metastasis and overall survival in early breast cancer. However, distant relapses may occur in patients with no DTC detected at time of primary cancer. In this study, we studied the impact of early breast cancer pathological features (including BM DTC status) on the incidence of CNS metastases. Methods: In a cohort (1998-2005) of 620 early breast cancer patients in whom BM DTC were detected using an anti-cytokeratin antibody (A45B/B3), 137 had a later metastatic relapse (median follow up 11y). Chi2 test were performed to compare patient with CNS metastasis and patients with other metastases locations. CNS metastasis survivals were estimated using Kaplan-Meier method and compared by log-rank test. Results: Distant metastases were diagnosed in 137 (22%) patients. In the course of the metastatic disease, 55 of these patients (40%) have been diagnosed with CNS metastases (parenchymal = 30, leptomeningeal = 10, both localizations = 15), as first metastatic or later event. Patients with CNS metastasis were mostly less than 50 years old (60% vs 38%, p = 0.01), pN0 (31% vs 10%, p = 0.002), hormonal receptor status negative (54% vs 30%, p = 0.007) and HER2 status positive (50% vs 22%, p = 0.01). Strikingly, although DTC detection was associated with development of distant metastasis in the whole cohort, the occurrence of CNS metastasis was found to be higher in patients who had no DTC detected at primary diagnosis (p = 0.016). From CNS metastasis, median survival was 7.8 months (8.3 months for parenchymal and 2.4 months for leptomeningeal recurrences). For HER2+ patients, the median survival after diagnosis of CNS metastasis was 16.6 months (N = 15) and 4.1 months for Her2- patients (N = 15). Conclusions: Our study suggests that cancer cells with epithelial differentiation, as detected in the BM, are less prone to CNS dissemination. This study also confirmed previously reported determinants of CNS metastases (age, RH-, HER2+) in the pre-adjuvant trastuzumab era, but also showed that the outcome of HER2+ patients with CNS relapse was longer, probably due to HER2 targeted therapy during metastatic course. Disclosure: All authors have declared no conflicts of interest.

Abstract OT1-1-10: CirCe T-DM1 phase II trial: Assessing the relevance of HER2-amplified circulating tumor cells as a tool to select HER2-negative metastatic breast cancer for treatment with T-DM1

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: T-DM1 has demonstrated its efficacy in the second line of HER2- positive metastatic breast cancer patients. Several studies reported that some breast cancers considered as HER2-negative do have HER2-positive circulating tumor cells (CTC). Our previous report (Lightart & Bidard, Ann Oncol 2013) showed that the reliability of such discrepancy between primary tumor and CTC is directly related to the number of CTC analyzed. This study aims at studying the efficacy of T-DM1 in this setting. Trial design: CirCe T-DM1 is a single arm two-step phase II multicenter study with adaptive design. Patients with HER2-negative measurable metastatic breast cancer will be screened by the FDA-approved CellSearch system, before the start of a second line treatment. HER2/CEP17 ratio will be quantified by FISH on CTC (Janssen Diagnostics). Patients with non HER2-amplified CTC or no CTC will be excluded from the study Patients with HER2-amplified CTC will be treated by T-DM1 single agent q3w, in either cohort “L” (low count: 1 to 4 HER2-amplified CTC) or “H” (high count: 5 or more HER2-amplified CTC). 14 patients (7L+7H) will be included in the first step. If needed, the second step will include 14 additional patients (7L+7H). Tumor response (per RECIST criteria) is the main objective of the trial. Eligibility criteria: main criteria are HER2-negative metastatic breast cancer; measurable disease progressing after a first line treatment; PS 0-1; criteria related to T-DM1 treatment and ethics. Only patients with HER2-positive CTC will be treated by T-DM1. Specific aim: this study will assess the response rate to T-DM1 in patients with HER2-amplified CTC and HER2-negative metastatic breast cancer, taking into account the number of HER2-amplified CTC detected (1-4 or 5+). Statistical methods: To design this adaptive study, response rates were estimated to be H0=5% (no efficacy of T-DM1) and H1=25% (efficacy of T-DM1). After the first step (N=7L and 7H patients): if no response is seen, the trial will be stopped, and considered as negative; if 3 or more responses are seen, we will conclude that the CTC FISH test is relevant to select patient for T-DM1 treatment, in either the L or/and H population, according to the observed pattern of responses; if 1 or 2 responses are observed, 14 more patients will be enrolled (7L+7H) in the second step of the trial. At the end of the second step, if 3 or less responses are observed, the trial will be considered as negative; if 4 or more responses are seen, we will conclude that the CTC FISH test is relevant to select patient for T-DM1 treatment, in either the L or/and H population, according to the observed pattern of responses. Based on the above-mentioned hypotheses and number of patients, the alpha risk was simulated to be of 6%, with a power of 94%. Accrual: the trial started in november 2013 in France. Up to 28 patients will be treated in this study. Citation Format: Francois-Clement Bidard, Yann de Rycke, Bernard Asselain, Paul Cottu, Manuel Rodrigues, Ronald Lebofsky, Jean-Yves Pierga. CirCe T-DM1 phase II trial: Assessing the relevance of HER2-amplified circulating tumor cells as a tool to select HER2-negative metastatic breast cancer for treatment with TDM1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT317. doi:10.1158/1538-7445.AM2014-CT317

Validation dans le temps d’un nomogramme prédictif de positivité du ganglion sentinelle axillaire en fonction des sous-types moléculaires de cancer du sein

Les sous-types moleculaires de cancer du sein ont des statuts axillaires differents. Un nouveau nomogramme incluant l’interaction entre les recepteurs aux oestrogenes (RO) et le statut HER2 a recemment ete publie et permet d’identifier, avant la chirurgie, les patientes ayant un haut risque d’atteinte du ganglion sentinelle axillaire (GS) [1]. L’objectif de notre etude etait de valider ce modele sur une population independante.