C Fontaine

Impact of Management Changes on Loco-Regional Control of Breast Carcinoma: A 30-year Single Institution Experience Breast Cancer: Basic and Clinical Research

Purpose: This institutional-based study aims to reflect changes in diagnosis, surgery, radiotherapy, systemic therapy by retrospectively analysing treatment modalities and outcome during the past 30 years of breast cancer. We hypothesized these changes result in better outcome. Material and methods: 2990 women are included, aged 18–95, no previous cancer, unilateral stage I-III primary breast tumors, breast-conserving surgery (BCS) or mastectomy (ME), postoperative radiotherapy (RT) and where indicated systemic treatment. Patients were divided in 3 cohorts stratified by year of diagnosis: 1984-1991, 1992- 1999 and 2000-2008. The interval of cohorts was based on institutional changes in systemic regimens. Results: Over time, median age at diagnosis was similar, patients >70 year increased (19.5 to 25.7%). Over the 3 cohorts: stage migration is observed, determination of tumor grading became routine, proportions of known ER/PR status increased. Over time an obvious shift to less mutilating surgery is observed. Systemic treatment increased significantly during the observed period. In stage I disease, overall (OS), local control (LC) and disease free survival (DFS) didn’t change. In stage II, a significant increase in 10 years OS and DFS (p= 0.02 and 0.001) is observed. In stage III we noticed a significant increase in 10 years DFS (p=0.04) and trend in increase of 10 years OS (p= 0.06). Local Recurrence free survival (RFS) didn’t change significantly for all stages. Conclusion: This study demonstrated an improved outcome for stage II and III over time in our population with the same local control. This is multifactorial, reflecting changes in diagnostic imaging, surgery and increased use of systemic therapy.

Abstract P5-16-06: Neoadjuvant weekly carboplatin and paclitaxel followed by dose dense epirubicin and cyclophosphamide in triple negative breast cancer patients: A single arm phase II study from the Belgian Society of Medical Oncology

Introduction: Triple negative breast cancer (TNBC) remains a challenging disease with dismal prognosis. Platinum analogs have not yet shown to improve long term outcome in this setting, but are associated with increased pathological complete response rate (pCR) at the cost of higher toxicity. Aim: To further increase or maintain the high pCR rate with platinum containing schedules while decreasing toxicity by administering low dose weekly carboplatin instead of high-dose 3 weekly carboplatin as in CALGB 40603.(1) Patients and methods: We evaluated the tolerability and the impact of the addition of weekly carboplatin (CP) to paclitaxel (P) and dose dense epirubicin-cyclofosfamide (EC) on pCR in an open-label multicenter phase II study in stage II/III TNBC patients (pts). Sixty three pts received dose dense paclitaxel (P:80mg/m2/wk) concurrent with carboplatin (CP: AUC=2) for 12 wks, followed by two-weekly epirubicin (E:90mg/m2) and cyclophosphamide (C:600mg/m2) for 4 cycles. The primary endpoint is pCR in the breast and axilla. Additionally treatment deliveryand adverse events are recorded. A correlative assessment of germline mutations in homologous recombination (HR) genes is planned. Pts are monitored for response by magnetic resonance and mammography and also for relapse free survival and time to treatment failure. The study size sample has been calculated according to the optimal Simon9s two-stage design method. The target sample size was 63 patients with 80% power to detect a pCR rate of ≥47% (α= 0.05). Results: Accrual to the study is completed with 63 eligible pts with operable, noninflammatory stage II and III TNBC included. Most patients were between 40 and 60 yrs old and were clinical stageT2 tumors. Half of the pts were clinically node + and 70% were G3. Sixty six percent had breast conserving surgery. Sixteen out of 26 (61.5%) of the currently evaluable pts achieved a pCR rate in the breast and axilla. The other ongoing patients have not yet reached this endpoint. Four out of 21 evaluable pts that completed the chemotherapy missed two or more doses of CP due to neutropenia(NP) G3/4(2), general deterioration G3(1) and polyneuropathy(PNP) G3(1) and seven pts needed one dose reduction of P and/or CP due to NP G3-4 (3-2) and PNP G2(1) and one abdominal infection. Conclusion: These preliminary data suggest that the addition of weekly carboplatinum to neoadjuvant paclitaxel and EC is feasible and has a promising pCR rate in the breast and axilla as high as 61.5% in early TNBC pts. More mature toxicity and outcome data and correlation with genome analysis will be presented. (1) Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once per week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603(Alliance) Sikov WM et al. J Clin Oncol 33:13-21; 2014. Citation Format: Fontaine C, Cappoen N, Renard V, Vuylsteke P, Van Den Bulck H, Glorieux P, t9Kint de Roodenbeke D, Dopchie C, Decoster L, Vanacker L, De Greve J, Awada A, Wildiers H. Neoadjuvant weekly carboplatin and paclitaxel followed by dose dense epirubicin and cyclophosphamide in triple negative breast cancer patients: A single arm phase II study from the Belgian Society of Medical Oncology [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-06.

Abstract P1-13-06: Correlation between aromatase-induced arthralgia and inflammatory cytokines in postmenopausal patients with early breast cancer treated with surgery followed by adjuvant hormone therapy: A prospective open-label single center study

Introduction: Nine randomized trials in early breast cancer(EBC) have demonstrated an advantage of aromatase inhibitors(AI’s) over tamoxifen in disease-free survival. Joint symptoms are common toxicities and lead to treatment interruption in up to 20% in case of severe aromatase-induced arthralgia(AIA). During menopause levels of markers of inflammation such as IL-1b, TNF-alpha and IL-6 increase. We hypothesized that estrogen deprivation by aromatase inhibition could be associated with similar changes in these markers and that this could play a role in AIA. In an earlier study, similar toxicities were observed in patients(pts) treated with a recombinant form of IL-6. In several cell types it has been shown that ligand activated estrogen receptor blocks nuclear factor kappa beta controlled gene transcription of IL-6. Aim of the study: We initiated a prospective open-label study to examine the role of inflammatory cytokines and other serum markers(CRP and hormones) in the pathogenesis of AIA. Methods: 29 evaluable postmenopausal pts with hormone sensitive, Her 2 negative EBC stage I-III, with baseline G0-1 arthralgia were included. Before chemotherapy, at baseline, at month 3, 6, 9, 12 and 18 after AI initiation, serum samples were taken for CRP and hormones (estradiol, androstenedion) and cytokines were analyzed with a human cytokine 25-plex panel. A detailed rheumatologic questionnaire and Visual Analog Scale(VAS) was performed at each visit. Arthralgia grading was assessed using the CTCAE criteria 4.0. The T-test and the Wilcoxon Signed Rank test were used to look for the difference in terms of IL-6, Il-1b, IL-8, TNF, CRP, estradiol and androstenedion between G0 versus G1-2-3 arthralgia. Results: The mean age was 56 yrs. (34-72yrs). All patients were treated with surgery followed by concomitant chemoradiation and letrozole (31) or anastrazole (1). In 16 pts G1 arthralgia was present before the start of the chemotherapy. Grade 2 and 3 arthralgia appeared at mth 3. The proportion of pts with grade 2 remained more or less the same, while grade 3 pts declined from month 6 onwards and disappeared at month 18. There was a significant correlation between the grade of arthralgia and the VAS score at all-time points (p Conclusion: This study indicates that both menopause and AIA have inflammatory mediators (IL6 and CRP) that correlate with the degree of lowering of estradiol levels. This is consistent with the regulation of IL-6 by the ligand activated ER through NFkB in vitro. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-06.

Abstract P1-13-05: A prospective study to evaluate joint changes by ultrasound and magnetic resonance imaging induced by adjuvant chemotherapy followed by aromatase inhibitors in postmenopausal early breast cancer patients developing G3 arthralgia

Introduction: Aromatase inhibitors (AI) are a well-established component of the adjuvant hormonal therapy in postmenopausal (PM) EBC patients (pts). AI have been associated with joint symptoms in 20 to 40% of pts adversely affecting quality of life and compliance. The subjective nature of these toxicities warrants objective correlates. In this study we have compared synovial changes on MRI with ultrasound (US). Aim of the study : The primary aim was to assess joint changes in PM EBC pts by MRI and US at baseline and at occurrence of arthralgia G3 during AI therapy. The secondary aim was to investigate the relationship between clinical severity of articular symptoms and markers of bone metabolism. Methods: PM EBC pts, stages I-III, with a grade 0, 1 arthralgia (CTCAE version 4.0) at baseline were recruited for the study. At baseline and at 3, 6, 9, 12 and 18 months (mths) a rheumatologic questionnaire was performed. At the same time points serum samples for bone markers (Ca, ostase, intact PTH, alkaline phosphatase and vit. D), rheumatoid factor (RF) and urine samples for urinary N-telopeptide (uNTX) were taken. Pain was assessed by the Visual Analog Scale (VAS). Before start of AI, osteoarthritis was quantified by plain radiography (hands, wrists and knees), joint changes were assessed baseline and at occurrence of arthralgia G3 by MRI and US (hands and wrists), and bone density by DEXA. Results: 29 evaluable PM EBC pts were included in the study. At baseline, 60% of the pts had a mean VAS score of 2 (0/10-5/10), which increased to 2.5 after the adjuvant chemotherapy and to 4.5 (0-8) at mth 12 (p = 0.013) of AI therapy, and subsequently dropped to 2.5 at mth 18 (p = 0.2). The most commonly affected joints at baseline were knees (47%), shoulders (41%), and ankles/feet (29%); whereas during AI therapy it involved mainly knees (53%), shoulders (46%) and hands/wrists (32%). Fifty percent of the pts had signs of osteoarthritis of the hands (25%), knees (16%) and both (8%) on plain radiographs obtained at baseline. Grade 0-1 arthralgia was not significantly correlated with the imaging of osteoarthritis or grade of osteoporosis. At baseline intra-articular fluid was detected on MRI of the hands/wrists in 6 pts, 14 pts had synovial changes and 4 had both. Six out of 29 pts had also signs of synovitis with hyperaemia on US before the start of an AI. G3 arthralgia occurred in five pts of which only three agreed to the repeat radiological imaging. In two of these pts a worsening of imaging both by MRI and US was observed, whereas in the third pt imaging was unchanged. Markers of bone metabolism and uNTX did not differ significantly between groups with arthralgia and without (p>0.05). RF was positive in only two pts, one with arthralgia G1 at baseline and one pt at the moment of G3 arthralgia. Conclusions: This study is the first to prospectively report on synovial changes by combined MRI and US before initiation of adjuvant AI in PM women and at occurrence of arthralgia G3. Only 17% of pts developed G3 arthralgia which corresponded to worsening imaging signs. From the small sample size it seems that baseline MRI changes predicts the development of G3 arthralgia with higher sensitivity than baseline US. Sensitivity of US improved during AI therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-05.

Abstract P6-09-07: Impact of comprehensive geriatric assessment on treatment decision and follow-up in older breast cancer patients

Purpose: This study aims to investigate the impact of comprehensive Geriatric Assessment (CGA) on treatment decisions in a large cohort of older breast cancer patients. We also studied the functional evolution during treatment and the development of severe toxicity in patients receiving chemotherapy and we looked for predictive baseline markers of functional decline and toxicity. Patients and methods: This study is part of a study on CGA in older cancer patients in 6 tumor types. We selected the breast cancer cohort for this presentation: 379 older breast cancer patients were recruited in 2 Belgian university hospitals. Patients aged 70 years or older with a newly diagnosed or progressive breast cancer for which treatment initiation or change was considered, were eligible. At baseline, an evaluation was performed of the oncological parameters as well as a CGA including geriatric screening with G8 and Flemish version of the TRST, pain, social situation, Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), presence of falls, MNA, GDS-15, MOB-T for fatigue, MMSE, polypharmacy, and Charlson Comorbidity Index (CCI). CGA results were communicated to the treating physician and after treatment decision, the physician was interviewed by a trained healthcare worker using a predefined questionnaire focusing on unknown geriatric problems revealed by CGA, subsequent planning of geriatric interventions, and impact on treatment decision. At 2–3 months follow-up, functionality was reassessed and severe toxicity in patients receiving chemotherapy (n = 98) was recorded. Predictors for functional decline (ADL increase of ≥2 points and IADL decrease of ≥1 point compared to baseline) and severe haematological and non-haematological toxicity were identified by multivariate analysis. Results: 79,2% of treating physicians were aware of CGA results at the time of treatment decision. CGA revealed unknown geriatric problems in 70,5% of cases, leading to geriatric intervention in 5,4% of patients. Treatment was adapted according to age and standard clinical approach (without CGA taken into account) in 41,1% of cases and CGA results led to an additional change of treatment decision in 5,4%. At follow-up, 47,9% of patients was dependent on at least one of the activities of ADL (compared to 54,1% at baseline) and 64,7% was dependent on at least one of IADL (compared to 58,1% at baseline). Functional decline at 2–3 months was predicted by baseline ADL, IADL and ECOG-PS, but no markers were found to predict chemotherapy toxicity (which occurred in 22/98 pts: 14 hematological toxicity gr III-IV, and 10 non-hematological toxicity gr III-IV) Conclusion: CGA revealed unknown information in the majority (70.5%) of breast cancer patients but led to a geriatric intervention and a change in treatment decision in a minority of pts (both 5.4%). Baseline functionality measures (ADL, IADL, ECOG-PS) were found to be predictive for functional decline at 2–3 months, but predictors for severe chemotherapy toxicity could not be identified. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-09-07.