Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy.The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up.Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years.No further treatment or 16-Gy boost, after BCS and 50-Gy WBI.Time to ipsilateral breast tumor recurrence (IBTR) as first event.The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present).The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately.clinicaltrials.gov Identifier: NCT02295033.
AbstractObjective Most patients receive whole breast radiotherapy in a supine position. However, two randomised trials showed lower acute toxicity in prone position. Furthermore, in most patients, prone positioning reduced doses to the organs at risk. To confirm these findings, we compared toxicity outcomes, photographic assessment, and dosimetry between both positions using REQUITE data.Methods REQUITE is an international multi-centre prospective observational study that recruited 2069 breast cancer patients receiving radiotherapy. Data on toxicity, health-related quality of life (HRQoL), and dosimetry were collected, as well as a photographic assessment. A matched case control analysis compared patients treated prone (n = 268) versus supine (n = 493). Exact matching was performed for the use of intensity-modulated radiotherapy, boost, lymph node irradiation, chemotherapy and fractionation, and the nearest neighbour for breast volume. Primary endpoints were dermatitis at the end of radiotherapy, and atrophy and cosmetic outcome by photographic assessment at two years.Results At the last treatment fraction, there was no significant difference in dermatitis (p = .28) or any HRQoL domain, but prone positioning increased the risk of breast oedema (p < .001). At 2 years, patients treated in prone position had less atrophy (p = .01), and higher body image (p < .001), and social functioning (p < .001) scores. The photographic assessment showed no difference in cosmesis at 2 years (p = .22). In prone position, mean heart dose (MHD) was significantly lower for left-sided patients (1.29 Gy vs 2.10 Gy, p < .001) and ipsilateral mean lung dose (MLD) was significantly lower for all patients (2.77 Gy vs 5.89 Gy, p < .001).Conclusions Prone radiotherapy showed lower MLD and MHD compared to supine position, although the risk of developing breast oedema during radiotherapy was higher. At 2 years the photographic assessment showed no difference in the cosmetic outcome, but less atrophy was seen in prone-treated patients and this seems to have a positive influence on the HRQoL domain of body image.Keywords: Breast cancerprone positionradiotherapy toxicityhealth-related quality of lifedosimetry Disclosure statementGhent University owns the patent application entitled Radiotherapy Board and Couch [WO2015144654A1] filed on March 25, 2014 for which LV is listed as inventor. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Data availability statementRaw data were generated by the REQUITE consortium. Derived data supporting the findings of this study are available from the corresponding author VV on request. External researchers can contact requite@manchester.ac.uk for further information on how to apply for access to the full REQUITE data (fees apply).Additional informationFundingREQUITE has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 601826. During the conduct of this work, Liv Veldeman was recipient of a Clinical Mandate of Stand up to Cancer (Flemish Cancer Society).
11042 Background: In MBC, adding X to T improves RR, TTP and OS; adding X to TH improves TTP. XT±H is appealing in early BC because H serum concentrations fall during the peri-operative period, potentially reducing the risk of overlapping cardiac toxicity with adjuvant anthracyclines. Methods: Pts with newly diagnosed invasive stage III inoperable BC (cT4 and/or cN2–3) received six 21d cycles of oral X 900 mg/m 2 bid d1–14 + iv T 36 mg/m 2 d1&8 (+ H on d1 in pts with HER2+ [IHC 3+/FISH+] tumors: 8 mg/kg cycle 1, 6 mg/kg cycles 2–6). After surgery, pts received 4–6 cycles of FEC100 and radiotherapy (+ hormone therapy and H when indicated). Clinical response was assessed after cycles 3 and 6, safety after each cycle, and pathological complete response (pCR: no residual invasive tumor in breast and axilla) after surgery. Results: 71 of 89 planned pts have completed XT±H (Table); 64 have undergone surgery (53 mastectomies, 9 wide excisions, 2 axillary lymph node dissections only). 51 pts are evaluable for safety. The most common treatment-related adverse events (AEs; G1- 2/G3) were stomatitis (61%/8%), nausea (61%/6%), diarrhea (41%/22%), fatigue (57%/4%), neuropathy (59%/0), lacrimation (57%/0) and hand- foot syndrome (33%/16%). Other G3 AEs were anorexia (14%) and vomiting (10%); neutropenic fever occurred in 4 pts (8%). 24 pts had a dose reduction for G2–3 AEs (X 47%, T 27%). 7 pts stopped therapy prematurely for AEs. No unexpected AEs occurred with anthracycline-based adjuvant therapy. Conclusions: Although all pts experienced at least one AE, toxicity was predictable and manageable with dose reduction. Based on the encouraging efficacy of XT+H in HER2+ pts, we are expanding this arm. [Table: see text] No significant financial relationships to disclose.
Abstract Background The introduction of multi-gene panel testing in the diagnosis of hereditary breast and ovarian cancer (HBOC) has led to an important increase in the detection of breast cancer predisposition genes other than BRCA1 and BRCA2. Methods All individuals who underwent HBOC-testing at our institution since the introduction of multi-gene panel testing were included (March 2016-August 2017). In this retrospective analysis, the BRCA Hereditary Cancer MASTR Plus® panel is used (Multiplicom, Belgium), with sequencing of BARD1, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, FAM175A, ATM, PALB2, STK11, MEN1, PTEN, CDH1, MUTYH, CHEK2, BLM, XRCC2, EPCAM, MLH1, MSH6, PMS2, MSH2. In breast cancer patients with a recurrent germline alteration, age and TNM stage at diagnosis, histological subtype, grade of differentiation and molecular surrogate subtype were recorded. Given the low numbers of TP53-carriers diagnosed by HBOC testing, also patients with a germline TP53-mutation diagnosed by targeted sequencing at our institution were included. Statistical analysis were performed with SPSS version 25. Results In 11.9 % of 2806 patients who underwent panel testing, a germline pathogenic alteration was detected. BRCA1 and BRCA2 were the most prevalent alterations, detected in respectively 3.35 and 2.92 % of patients. Germline alterations in CHEK2, ATM , PALB2 and TP53 were detected in respectively 2.5 %, 1.1 %, 0.5 % and 0.1 %. In 1 % of patients, germline alterations were retrieved that only contribute to ovarian cancer risk (BRIP, RAD51C, RAD51D). Germline DNA mismatch repair alterations were detected in 0.39 % of patients. The median age at onset of breast cancer in patients with germline CHEK2-, ATM-, PALB2- and TP53-mutations was 47, 53, 39 and 33 years respectively. The age of breast cancer diagnosis in patients with germline TP53-alterations was significantly younger compared to patients with CHEK2-mutations (p = 0.01), ATM-mutations (p = 0.01) and PALB2-mutations (p = 0.04). In situ carcinomas were diagnosed in respectively 9 %, 11 % and 11 % of patients with CHEK2-, PALB2- and TP53-mutations. Patients with CHEK2, ATM, PALB2 and TP53-alterations were diagnosed with ≥T3-tumors in respectively 13 %, 12 %, 33 % and 22 %. Nodal status at diagnosis was negative in 40-60 % in these 4 subgroups. Upfront metastatic disease was diagnosed only in 2/43 CHEK2-carriers. More than half of the breast cancer diagnoses were luminal tumors in CHEK2-, ATM- and PALB2-carriers, while cases with germline TP53-alterations only presented with luminal cancers in 22 % in our series. Conclusion Almost half of the pathogenic mutations detected in HBOC-genes are alterations in genes other than BRCA1 and BRCA2. CHEK2-mutations are by far the most prevalent, followed by ATM, PALB2 and TP53. The range of the CHEK2- and ATM-population was wider then expected at the lower-age boundary. The age of breast cancer diagnosis in patients with germline TP53-mutations was significantly younger compared to patients with CHEK2-, ATM- and PALB2-mutations. The distribution of the histological subtypes and grade of differentiation was not suggestive of a specific correlation with germline mutation status. Citation Format: Hoste G, D'Hoore P, Legius E, Van Buggenhout G, Floris G, Wildiers H, Han SN, Van Nieuwenhuysen E, Berteloot P, Smeets A, Nevelsteen I, Weltens C, Janssen H, Van Limbergen E, Neven P, Punie K. Hereditary breast cancer beyond BRCA: Clinical and histopathological characteristics in patients with germline CHEK2, ATM, PALB2 and TP53-mutations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-05.
Abstract Background and objective: Invasive micropapillary carcinoma (IMPC) of the breast is a special variant of breast carcinoma with a unique morphology. Data about long-term outcome are conflicting and reports on stromal tumor infiltrating lymphocytes (sTILs) and their correlation with prognosis are scarce. In this retrospective cohort study we aimed to describe clinical and pathological features of IMPC, including sTILs assessment and immunohistochemistry studies, and their correlation with long-term outcome. Materials and methods: Patients with stage I-III IMPC (pure and mixed forms) who underwent upfront surgery at our institution between 2000 and 2016 were included. All patients signed informed consent. Standard clinico-pathological features and follow-up data to calculate distant relapse-free interval and breast cancer-specific survival were obtained from clinical records. Pathologic review of representative H&E-slides of the resection specimens included evaluation of sTILs and assessment of the micropapillary component. Surrogate molecular subtypes were based on receptor-status and histological grade. Using tissue microarrays we assessed by immunohistochemistry the pattern of staining of P53, and scored semi-qualitatively the expression of Bcl2, PAX8 and WT1. The association between predictors and outcome is analyzed using the Fine and Gray model, accounting for other-cause death as competing event. All tests are two-sided, assuming a 5% significance level. The sample size did not allow multivariate analysis. Results: We included 111 patients (median age 61,5 years; range 33-88). Luminal surrogate subtypes were most prevalent with 51 luminal A-like, 41 luminal B-like, 12 luminal HER2+, 5 HER2+ and 2 triple negative IMPC. 89% of patients had a T1 or T2 tumor and 50% of IMPC were poorly differentiated. Lymph node involvement was present in 59% and lymphovascular invasion in 44% of cases. Adjuvant chemotherapy, radiotherapy and endocrine therapy was administered in 47%, 87% and 90% of patients, respectively. Of all cases 59% were pure IMPC. Standard clinico-pathological features were comparable between pure and non-pure IMPC. sTILs were classified as low (<30%), intermediate (30-50%) and high (>50%) in 78%, 14% and 8% of specimens respectively. Comparison between surrogate subtypes showed higher sTILs (p=0.025) and a higher likelihood of aberrant P53 expression (p<0.001) in HER2+ compared to luminal A-like subtype. Immunohistochemistry studies performed on 105 samples with enough material showed aberrant P53 expression in 10% and WT1 nuclear expression in 7% of cases. Pax8-staining was negative in all IMPC in this cohort. Bcl-2 expression was strongly related to all luminal subtypes (p<0.03). After a median follow-up of 100 months, we observed 8 distant relapses (7,2%) and 3 breast cancer-related deaths (2,7%). All events occurred in non-pure IMPC. Surrogate subtypes for patients with distant relapses where luminal A-like in 4 patients while the other subtypes where each observed in 1 patient. Five out of eight patients with distant relapse had received prior adjuvant chemotherapy. Six had lymph node involvement. Higher median sTILs was correlated with worse distant relapse-free interval (HR=1.55; p=0.0172) and breast cancer-specific survival (HR=2.10; p<0.001). Conclusions: Standard clinico-pathological features were similar in pure and non-pure IMPC. Despite high proportion of grade 3 differentiation and lymph node involvement, we observed a low rate of distant metastasis and within the pure IMPC (59% of patients), no distant relapses occurred. These findings could be explained by the high proportion of luminal-A like tumors in our cohort and need confirmation. Higher sTILs was associated with worse outcome in this IMPC cohort, confirming previously published observations. Citation Format: Kevin Punie, Frederik Deman, Annouschka Laenen, Timothy Faes, Hans Wildiers, Ann Smeets, Ines Nevelsteen, Chantal Van Ongeval, Adinda Baten, Melissa Christiaens, Eva Oldenburger, Hilde Janssen, Caroline Weltens, Tatjana Geukens, Nynke Willers, Jan Ardui, Hava Izci, Laurence Slembrouck, Patrick Neven, Christine Desmedt, Giuseppe Floris. Clinical and pathological features of invasive micropapillary carcinoma of the breast and correlation with prognosis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-31.
Inflammatory breast cancer (IBC) is a rare but aggressive form of breast cancer. It is mainly a clinical diagnosis. The aim of this study was to compare IBC to clinically diagnosed noninflammatory locally advanced nonmetastatic breast cancer, also called cLABC.One hundred and eight patients were studied: 49 with IBC and 59 with cLABC. The following features were analyzed: age at diagnosis, body mass index (BMI), axillary lymph node status (cN), estrogen receptor status (ER), progesterone receptor status (PR), HER2 status, histological tumor grade and subtype. Short-term disease-free (DFS) and overall survival (OS) were also assessed in both groups.Compared with cLABC, IBC was less often PR positive (41.7 vs. 66.1%, p = 0.01) and showed a trend to be more often HER2 positive (34.7 vs. 19.3%, p = 0.07). The 3-year DFS was 63 and 77%, respectively, for IBC and cLABC (p = 0.01); these figures were 83 and 85% for OS (p = 0.17). No significant differences in age at diagnosis, ER, cN, BMI, histological tumor grade or subtype were demonstrated.Compared to cLABC, IBC are more frequently PR negative, have a worse DFS, and have a tendency to be more often HER2 positive. These data reinforce the idea of IBC being a distinct biological entity compared to noninflammatory breast cancer.
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