Outcomes and toxicity of concurrent CDK4/6 inhibitor and locoregional radiotherapy for patients with de novo metastatic breast cancer.

The objective of the present study was to assess the outcomes and toxicity of patients treated with concurrent administration of CDK4/6 inhibitors (CDK4/6i) and locoregional radiation therapy (RT), including the breast with a boost or the thoracic wall after mastectomy and the regional lymph node areas. We retrospectively analyzed data from 27 patients with hormone receptor-positive, HER2-negative de novo metastatic breast cancer treated with CDK4/6i and concomitant locoregional RT in 2017/2022. Survival rates were calculated by Kaplan-Meier method. Prognostic factors were tested with log-rank test. CDK4/6i was used as the first systemic metastatic treatment for all the patients, and the median overall treatment time was 26 months. The median time from initiation of CDK4/6i to the start of RT was 10 months (IQR: 7-14 months). The median duration of concomitant CDK4/6i and RT administration was 21 days (IQR: 14.5-23 days). After a median follow-up of 19 months (IQR: 14-36 months), 1 patient died, 11/27 had distant metastases and 1 patient had local recurrence, respectively. The 1- and 3-years progression-free survival (PFS) were 61.4% (95% CI: 45.1%-83.7%) and 53.7% (35.8%-80.5%), respectively. The acute toxicities most observed during RT were neutropenia (44%) and dermatitis (37%). Dermatitis was significantly more frequent in patients with large target volumes (CTV > 911 cc and PTV > 1285 cc). CDK4/6i had to be discontinued in five patients during RT (due to toxicity in three cases and disease progression in two cases). One patient has developed grade 2 late pulmonary fibrosis. Finally, our study demonstrated that concurrent administration of locoregional RT and CDK4/6i did not induce severe late toxicity for most patients.

Clinical outcomes of curative-intent multimodal management of chemorefractory nonmetastatic inflammatory breast cancer.

INTRODUCTION: Chemorefractory nonmetastatic inflammatory breast cancer (IBC) which progresses under neoadjuvant chemotherapy poses specific therapeutic challenges: either pursuing a curative-intent treatment with a salvage combination of radiotherapy and surgery or switching to second-line systemic treatments despite the absence of metastasis. Due to the rarity of this situation, no specific management guidelines exist and the outcomes of these patients remain uncertain. In this retrospective observational study, we aimed to report the clinical outcomes of patients treated in a curative intent for chemorefractory nonmetastatic IBC, with a multimodal salvage treatment combining radiotherapy and surgery. MATERIALS AND METHODS: This single-center retrospective observational study included all chemorefractory nonmetastatic IBC treated at the Institut Curie (Paris, France). Overall survival (OS), disease-free survival (DFS), and locoregional relapse-free survival (LRRFS) were calculated from the time of diagnosis and from the time of neoadjuvant chemotherapy interruption. RESULTS: Between January 2010 and January 2018, 7 patients presented with chemorefractory nonmetastatic IBC with a progressive disease during neoadjuvant chemotherapy. Overall, chemorefractory IBC patients were young (median age of 50 years), had a good performance status, and usually presented with node-positive tumors characterized by a combination of adverse histological factors such as triple-negative breast cancer (TNBC), grade III, and high proliferation index. From the date of pathological diagnosis, 1­year OS, DFS, and LRRFS were 64.3%, 53.6%, and 71.4%, respectively. From the date of neoadjuvant chemotherapy interruption, 1­year OS, DFS, and LRRFS were 47.6%, 19.0%, and 45.7%, respectively, and median OS, DFS, and LRRFS were 8.3, 5.0, and 5.0 months, respectively. CONCLUSION: The prognosis of chemorefractory nonmetastatic IBC treated with a multimodal approach combining surgery and radiotherapy is particularly reserved, despite the curative intent of the salvage treatment and the lack of distant metastasis at the time of treatment. Optimal treatment modalities are still to be defined in this rare but critical presentation of IBC.

The role of post-mastectomy radiotherapy in elderly patients with 1-3 positive lymph nodes breast cancer: An International Retrospective Double-Center Study.

This study evaluated the role of post-mastectomy radiotherapy (PMRT) in 111 patients with 1-3 positive nodes, aged 65 years or above between 2007 and 2013. In total, 64 received PMRT. The PMRT group had more aggressive tumor. Three patients suffered locoregional recurrences in each group at median follow-up of 50 months. PMRT has no significant impact on distant disease-free survival (DDRFS), recurrence-free survival (RFS) and overall survival (OS). In patients with tumors >5 cm, PMRT significantly improved DDRFS, RFS, and marginally prolonged OS. These results supported that PMRT should not be compromised in all elderly patients, especially in those with tumor >5 cm.

The place of the boost in the breast cancer treatment: State of art.

Several randomized controlled trials have demonstrated the benefit of a boost to the tumor bed (TB) to reduce the risk of ipsilateral breast tumor recurrence. Recent technological progress has facilitated improved conformation of isodoses around the target volume. The accuracy and reproducibility of TB delineation have become even more essential. The purpose of this study is to review the extant knowledge on the boost delineation in breast cancer, focusing on interobserver variability (IOV) and the influence of various factors, such as the presence of clips or different imaging modalities to improve IOV. Most studies investigating IOV for boost delineation have shown poor reproducibility (with comparison indices such as the dice similarity index around 0.5). Clips in the lumpectomy cavity (LC), postoperative fluid accumulation in the LC and/or high cavity visualization score appeared to be associated with improved IOV. Likewise, the use of preoperative imaging (CT and/or MRI) may also be useful in improving the accuracy of TB definition but without any real gain in terms of IOV. Moreover, the delineation of boost has become even more challenging since the development of oncoplastic surgery. To improve the reproducibility and the accuracy of boost delineation, this review suggests that within each center, a group of multidisciplinary experts, including surgeons, radiation oncologists, pathologists, and radiologists, should convene to develop local guidelines, which may include the choice of preoperative imaging, the number and location of surgical clips, pathological margins, and orientation. The elaboration of contouring atlas is certainly of great assistance.

[How to improve the surgical trials quality in daily practice]. / Comment améliorer la qualité méthodologique et l'adoption en routine des résultats des essais chirurgicaux ?

Surgical studies have specific issues, such as quality assurance on procedures, standardization of techniques, surgeon effect, timing of randomization, blinding respect or choice of the reference arm. All these difficulties conducted to criticism many trials, and lack of results implementation. Indeed, adherence to methodological guidelines is often poor. Twelve recommendations were recently issued by the JAMA surgery revue for good practice in surgical studies to improve the quality of surgical trials in general and surgical oncology. We detail here the main issues of surgical trials in gynaecological oncology surgery, as well as possibilities of improvement for future studies.

Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer: The Phase 1 Olaparib and Radiation Therapy for Triple-Negative Breast Cancer Trial.

Importance: Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear. Objective: To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy. Design, Setting, and Participants: This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions. Interventions: Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease. Main Outcomes and Measures: Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS). Results: Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS. Conclusions and Relevance: The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03109080.

Radiotherapy in the Management of Non-Metastatic Inflammatory Breast Cancers: A Retrospective Observational Study.

(1) Background: Inflammatory breast cancers (IBC) are characterized by a poor prognosis. This retrospective study aims to describe the clinical outcomes of non-metastatic IBC patients treated with a multidisciplinary approach with neo-adjuvant chemotherapy, surgery, and radiotherapy. (2) Methods: This single-center retrospective study included all women patients diagnosed with non-metastatic IBC between January 2010 and January 2018 at the Institut Curie (Paris, France) and treated with neoadjuvant chemotherapy, surgery, and radiotherapy. Overall survival (OS), disease-free survival (DFS), and locoregional free survival (LRRFS) were calculated from the time of diagnosis. Prognostic factors for patient survival were analyzed based on univariate and multivariate regressions. (3) Results: We identified 113 patients with a median age of 51 years. 79.7% had node-positive tumors; triple-negative breast cancers (TNBC) represented 34.6% of the cases. A large majority of patients (91.2%) received adjuvant post-mastectomy while ten patients (8.8%) received preoperative radiotherapy. Non-pathological complete response (non-pCR) was observed in 67.3% of patients. Radiotherapy delivered a median dose of 50 Gy to the breast or the chest wall in 25 fractions. With a median follow-up of 54 months, 5-year OS, DFS and LRRFS were 78% (CI: 70.1-86.8%), 68.1% (59.6-77.7%), and 85.2% (78.4-92.7%), respectively. In multivariate analysis, non-pCR was an adverse prognosis factor for OS, DFS, and LRRFS; pre-operative radiotherapy was an adverse prognosis factor for OS and DFS. Radiation-related adverse events were limited to acute skin toxicity (22% of Grade 2 and 2% of grade 3 dermatitis); no late radiation-induced toxicity was reported. (4) Conclusions: High locoregional control could be achieved with multidisciplinary management of non-metastatic IBC, suggesting the anti-tumor efficacy of radiotherapy in this rare but pejorative clinicopathological presentation. While comparing favorably with historical cohorts, OS and DFS could be potentially improved in the future with the use of new systemic treatments, such as PARP-inhibitors or immunotherapy.

Neoadjuvant Concurrent Radiotherapy and Chemotherapy in Early Breast Cancer Patients: Long-Term Results of a Prospective Phase II Trial.

Background: Neoadjuvant concurrent radiochemotherapy makes it possible to increase the breast conservation rate. This study reports the long term outcome of this treatment. Methods: From 2001 to 2003, 59 women with T2-3 N0-2 M0 invasive breast cancer (BC) not amenable to upfront breast conserving treatment (BCS) were included in this prospective, non-randomized phase II study. Chemotherapy (CT) consisted of four cycles of continuous 5-FU infusion and Vinorelbine. Starting concurrently with the second CT cycle, normofractionated RT was delivered to the breast and LN. Breast surgery was then performed. Results: Median follow-up (FU) was 13 years [3-18]. BCS was performed in 41 (69%) patients and mastectomy in 18 patients, with pathological complete response rate of 27%. Overall and distant-disease free survivals rates at 13 years were 70.9% [95% CI 59.6-84.2] and 71.5% [95% CI 60.5-84.5] respectively. Loco regional and local controls rates were 83.4% [95% CI 73.2-95.0] and 92.1% [95% CI 83.7-100], respectively. Late toxicity (CTCAE-V3) was assessed in 51 patients (86%) with a median follow-up of 13 years. Fifteen presented grade 2 fibrosis (29.4%), 8 (15.7%) had telangiectasia, and 1 had radiodermatitis. Conclusions: This combined treatment provided high long-term local control rates with limited side-effects.

Breast Magnetic Resonance Image Analysis for Surgeons Using Virtual Reality: A Comparative Study.

PURPOSE: The treatment of breast cancer, the leading cause of cancer and cancer mortality among women worldwide, is mainly on the basis of surgery. In this study, we describe the use of a medical image visualization tool on the basis of virtual reality (VR), entitled DIVA, in the context of breast cancer tumor localization among surgeons. The aim of this study was to evaluate the speed and accuracy of surgeons using DIVA for medical image analysis of breast magnetic resonance image (MRI) scans relative to standard image slice-based visualization tools. MATERIALS AND METHODS: In our study, residents and practicing surgeons used two breast MRI reading modalities: the common slice-based radiology interface and the DIVA system in its VR mode. Metrics measured were compared in relation to postoperative anatomical-pathologic reports. RESULTS: Eighteen breast surgeons from the Institut Curie performed all the analysis presented. The MRI analysis time was significantly lower with the DIVA system than with the slice-based visualization for residents, practitioners, and subsequently the entire group (P < .001). The accuracy of determination of which breast contained the lesion significantly increased with DIVA for residents (P = .003) and practitioners (P = .04). There was little difference between the DIVA and slice-based visualization for the determination of the number of lesions. The accuracy of quadrant determination was significantly improved by DIVA for practicing surgeons (P = .01) but not significantly for residents (P = .49). CONCLUSION: This study indicates that the VR visualization of medical images systematically improves surgeons' analysis of preoperative breast MRI scans across several different metrics irrespective of surgeon seniority.

Management of operable invasive breast cancer in women over the age of 70: long-term results of a large-scale single-institution experience.

BACKGROUND: The treatment of choice for elderly women with breast cancer remains controversial. This retrospective analysis of a cohort from a single institution was designed to evaluate whether such patients are really undertreated because of their age and to reappraise their usual management. METHODS: The characteristics of 538 patients aged > or = 70 years with operable breast cancer, treated between 1995 and 1999, were retrospectively analyzed comparing patients aged 70 to 75 years (group I, n = 288), 75 to 80 years (group II, n = 156), and > or = 80 years (group III, n = 94). Cause-specific survival, distant recurrence-free interval, and local control were estimated by the Kaplan-Meier method and compared by log rank test. Multivariate analysis used Cox regression. RESULTS: In group III, tumors were more frequently T2 than T1 (P < 0.0001) and estrogen receptor negative (P = 0.045) than in groups I and II. Surgery was performed in 94.6% of patients, breast-conserving in 72.1% (62% in group III; P = 0.0015) with axillary dissection in 89.2% (77% in group III; P = 0.0015); 100% received radiotherapy after lumpectomy (hypofractionated in 63% of group III; P < 0.0001). Adjuvant hormone therapy and chemotherapy were administered to 57 and 3.7% of patients, respectively. At 7 years, no difference in the three groups was observed for cause-specific survival (91% for group I, 89% for group II, 86% for group III) distant recurrence-free interval, and local control (>90%). CONCLUSIONS: Elderly patients with operable breast cancer who are completely and correctly treated with realistic treatment options that are based on surgery and adjuvant radiotherapy have a similar chance of being cured as younger patients.

Photons Without Bolus Versus Electrons With Bolus After Upfront Mastectomy Without Immediate Reconstruction in Breast Cancer Patients.

PURPOSE: To evaluate locoregional control and outcome after mastectomy in patients treated with postmastectomy highly conformal electron radiation therapy (PMERT) with bolus compared with patients treated by highly conformal photon radiation therapy (PMPhRT) without bolus in the adjuvant setting of nonmetastatic breast cancer. METHODS AND MATERIALS: We studied women undergoing PMRT without immediate reconstruction for breast cancer before 2012 in 2 sites of our hospital using 2 different techniques. All patients received 50 Gy in 25 fractions. Patients previously treated by neoadjuvant chemotherapy were excluded. RESULTS: Among the 807 patients, 583 received PMERT and 224 received PMPhRT. The median follow-up was 64 months. Patients in the PMERT group had a median age of 52.7 years (range, 26-91 years), 6.9% were triple-negative, 16.3% were HER2-positive, and 58.6% had multifocal lesions. Patients in the PMPhRT group had a median age of 56.4 years (28-89), 8.5% were triple negative, 12.9% were HER2-positive, and 55.8% had multifocal lesions. Lymph node involvement was observed in 66% and 72.8% of cases (P = .07) treated with PMERT and PMPhRT, respectively. No significant difference in overall survival was observed between the 2 groups (hazard ratio [HR], 1.2; 95% CI, 0.67-2.13; P = .54). The risk of locoregional recurrence, estimated using the Fine-Gray method, was significantly higher with PMPhRT than with PMERT (subdistribution HR, 3.62; 95% CI, 1.07-12.3; P = .04), corresponding to a 5-year LRR rate of 0.53% (95% CI, 0-1.12%) for PMERT and 2.52% (95% CI, 0.05%-4.6%) for PMPhRT. CONCLUSIONS: A higher risk of local recurrence was observed in the PMPhRT without bolus group compared with the PMERT with bolus group. Prospective randomized trials are needed to confirm these findings.

How to boost the breast tumor bed? A multidisciplinary approach in eight steps.

PURPOSE: To describe a new procedure for breast radiotherapy that will improve tumor bed localization and radiotherapy treatment using a multidisciplinary approach. PATIENTS AND METHODS: This pilot study was conducted by departments of radiation oncology, surgery, and radiology. A new procedure has been implemented, summarized as eight steps: from pre-surgery contrast CT to surgery, tumor bed planning target volume (PTV) determination, and finally breast and tumor bed irradiation. RESULTS: Twenty patients presenting with T1N0M0 tumors were enrolled in the study. All patients underwent lumpectomy with the placement of surgical clips in the tumor bed region. During surgery, 1 to 5 clips were placed in the lumpectomy cavity before the plastic procedure. All patients underwent pre- and postoperative CT scans in the treatment position. The two sets of images were registered with a match-point registration. All volumes were contoured and the results evaluated. The PTV included the clips region, the gross tumor volume, and the surgical scar, with an overall margin of 5-10 mm in all directions, corresponding to localization and setup uncertainties. For each patient the boost PTV was discussed and compared with our standard forward-planned PTV. CONCLUSIONS: We demonstrate the feasibility of a tumor bed localization and treatment procedure that seems adaptable to routine practice. Our study shows the advantages of a multidisciplinary approach for tumor bed localization and treatment. The use of more than 1 clip associated with pre- to postoperative CT image registration allows better definition of the PTV boost volume.

Outcomes of postoperative radiation therapy for breast cancer in older women according to age and comorbidity status: An observational retrospective study in 752 patients.

OBJECTIVES: The aim of this study was to assess efficacy, tolerability, and the impact of comorbidities on outcomes in older women treated by radiation therapy (RT) for non-metastatic breast cancer. MATERIALS AND METHODS: Women aged ≥70 years at diagnosis who received postoperative RT for primary non-metastatic BC between 2003 and 2009 were retrieved from the Institut Curie registry. We calculated the Charlson Comorbidity Index (CCI) for each patient. We analyzed overall survival (OS), progression free survival (PFS), and acute and late toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. RESULTS: A total of 752 patients were included in this study. Median age at diagnosis was 75 years [70-93.3]. With a median follow-up of 7.3 years [0.4-12.9], OS and PFS at 5 years were 87.2% CI95%[84.8-89.8] and 85.7% CI95%[83.1-88.3], respectively. OS at 5 years was statistically different according to the CCI: 90.7% CI95%[87.6-93.9] for a CCI of 0, 85.8% CI95%[81.8-90.1] for a CCI of 1, and 79.1% CI95%[71.1-87.9] for a CCI ≥ 2 (p < 0.01, log-rank test), respectively. Similar results were found for PFS (p < 0.05, log-rank test). Most (23.3%) of the patients had no toxicities; of those who experienced side-effects, the majority were grade I or II (96.9%). CONCLUSION: Postoperative RT for non-metastatic BC in older women is effective and well-tolerated. Outcome is impacted by age and comorbidities, which are clear independent prognostic factors.

Responses to concurrent radiotherapy and hormone-therapy and outcome for large breast cancers in post-menopausal women.

INTRODUCTION: This study aimed to evaluate responses and outcome of hormone-therapy (HT) and radiotherapy (RT) given concurrently for large breast cancers in post-menopausal women. MATERIAL AND METHODS: Forty-two breast carcinomas in 41 women were treated with HT and concurrent RT to the breast +/- lymph node bearing areas. For 30 tumours this was followed by breast surgery (with axillary lymph node dissection when the axilla had not been irradiated). RT delivered a median dose to the tumour of 50 Gy (48-66) and 75 Gy (65-84) for, respectively, preoperative and exclusive RT-HT. Median follow-up was 64 months. RESULTS: Out of 42 clinically assessable tumours (after a mean dose of 50 Gy), 9 tumours (21%) had complete clinical responses, 24 (57%) partial responses, 9 (21%) stable disease. Breast-conserving surgery or exclusive RT-HT was possible in 74% of tumours. For 29 patients who underwent breast surgery, the rate of pathological complete responses was 17%. At 50 Gy no skin toxicity higher than grade 2 occurred. Five year OS, RFS and local control were, respectively, 85%, 84% and 97%. Lymphoedema occurred in one patient. CONCLUSION: Concurrent association of RT-HT demonstrated good efficacy, both in terms of clinical and pathological complete responses. It allowed breast conservation with acceptable tolerance and good 5-year local control.

Long-Term Results of a Highly Performing Conformal Electron Therapy Technique for Chest Wall Irradiation After Mastectomy.

PURPOSE: To evaluate locoregional control and survival after mastectomy, as well as toxicity, in patients irradiated by a previously described postmastectomy highly conformal electron beam radiation therapy technique (PMERT). METHODS AND MATERIALS: We included all women irradiated by postmastectomy electron beam radiation therapy for nonmetastatic breast cancer between 2007 and 2011 in our department. Acute and late toxicities were retrospectively assessed using Common Terminology Criteria for Adverse Events version 3.0 criteria. RESULTS: Among the 796 women included, 10.1% were triple-negative, 18.8% HER2-positive, and 24.6% received neoadjuvant chemotherapy (CT). Multifocal lesions were observed in 51.3% of women, and 64.6% had at least 1 involved lymph node (LN). Internal mammary chain, supraclavicular, infraclavicular, and axillary LNs were treated in 85.6%, 88.3%, 77.9%, and 14.9% of cases, respectively. With a median follow-up of 64 months (range, 6-102 months), 5-year locoregional recurrence-free survival and overall survival were 90% (95% confidence interval 88.1%-92.4%) and 90.9% (95% confidence interval 88.9%-93%), respectively. Early skin toxicity was scored as grade 1 in 58.5% of patients, grade 2 in 35.9%, and grade 3 in 4.5%. Concomitant CT was associated with increased grade 3 toxicity (P<.001). At long-term follow-up, 29.8% of patients presented temporary or permanent hyperpigmentation or telangiectasia or fibrosis (grade 1: 23.6%; grade 2: 5.2%; grade 3: 1%), with higher rates among smokers (P=.06); 274 patients (34.4%) underwent breast reconstruction. Only 24 patients (3%) had early esophagitis of grade 1. Only 3 patients developed ischemic heart disease: all had been treated by anthracycline-based CT with or without trastuzumab, all had been irradiated to the left chest wall and LN, and all presented numerous cardiovascular risk factors (2-4 factors). CONCLUSIONS: This study demonstrated the good efficacy of this technique in terms of locoregional control and survival, and good short-term and long-term safety. Longer follow-up is required to analyze chronic cardiac events.

CT-scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning.

BACKGROUND AND PURPOSE: To evaluate the influence of the position and the exact localizations of supra clavicular nodes (SCN) and internal mammary chain (IMC) and their variability among patients in order to improve treatment planning in breast cancer (BC) patients. PATIENTS AND METHODS: A total of 46 CT scans of the chest were examined. All patients were female treated with breast conserving surgery and radiotherapy. The study was divided into two phases. The first consisted of measurements on 20 diagnostic CT scans, performed in the supine position with both arms over the head. All patients received contrast. This first phase was performed as a training program for radiologist and radiation oncologist to prepare for the second phase of the study: 26 CT scans in treatment position on angled board without injection. For this second group, patients had one arm raised above the head (treated side) and the other kept by the side (contralateral side). Measurements were performed on both sides to evaluate the influence of the arm position. The depths of IM- and SC vessels were measured at five points: (1) the origin of the internal mammary artery, (2) the sterno-clavicular articulation, (3-5) the first, second and third rib interspaces (RI). Measurements of the depth and of the distance between the internal mammary vessels and the middle axis of the sternum were obtained using electronic calipers on a PACS workstation. RESULTS: There were important individual variations of the depth of SCN, as follows: 20-84 mm (diagnostic) and 19-64 (treatment position). No differences in the depth of the IMC were found between treated and contralateral side at the region of the I, II, and III rib interspaces. The lateral margin of the IMC was never more than 40 mm from the middle axis of the sternum (I, II, III rib interspaces). There was no difference in the lateral limits of IMC (the distance between the IM vessels and the middle axis of the sternum) between the two sides: treated and contralateral. CONCLUSIONS: This study shows the importance of the patients' individual anatomy, their position and the large variability in the depth of SCN. It is important to visualize these regions to permit individual dosimetric optimization.

Gain-of-function Prolactin Receptor Variants Are Not Associated With Breast Cancer and Multiple Fibroadenoma Risk.

CONTEXT: In a cohort of 95 women with multiple breast fibroadenomas (MFAs), we recently identified patients harboring germline heterozygous variants of the prolactin receptor (PRLR) exhibiting constitutive activity (PRLRI146L and PRLRI176V). OBJECTIVE: This study sought to better delineate the potential role of PRLR gain-of-function variants in benign and malignant mammary tumorigenesis. DESIGN: This was an observational study and transgenic mouse model analysis. SETTING: The study took place at the Department of Endocrinology, Reproductive Disorders and Rare Gynecologic Diseases, Pitié Salpêtrière, Paris, and Inserm Unit 1151, Paris. PATIENTS OR OTHER PARTICIPANTS: We generated a second MFA cohort (n = 71) as well as a group of control subjects (n = 496) and a cohort of women with breast cancer (n = 119). We also generated two transgenic mouse models carrying the coding sequences of human PRLRI146L or PRLRWT. INTERVENTION: We aimed to determine the prevalence of PRLR variants in these three populations and to uncover any association of the latter with specific tumor pattern, especially in patients with breast cancer. RESULTS: This study did not highlight a higher prevalence of PRLR variants in the MFA group and in the breast cancer group compared with control subjects. Transgenic mice expressing PRLRI146L exhibited very mild histological mammary phenotype but tumors were never observed. CONCLUSION: PRLRI146L and PRLRI176V variants are not associated with breast cancer or MFA risk. However, one cannot exclude that low but sustained PRLR signaling may facilitate or contribute to pathological development driven by oncogenic pathways. Long-term patient follow-up should help to address this issue.

Long-term prognostic performance of Ki67 rate in early stage, pT1-pT2, pN0, invasive breast carcinoma.

BACKGROUND: Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1-pT2, pN0) breast cancer patients. METHODS: 456 patients treated in 1995-1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed. RESULTS: All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5-191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20%) Ki67 rate [HR = 3 (1.8-4.8), p<10e-06] and HG3 [HR = 4.4 (2.2-8.6), p = 0.00002] were associated with an increased rate of distant relapse. In multivariate analysis, the Ki67 remained the only significant prognostic factor in the subgroups of ER positive HER2 negative [HR = 2.6 (1.5-4.6), p = 0.0006] and ER positive HER2 negative HG2 tumors [HR = 2.2 (1.01-4.8), p = 0.04]. CONCLUSIONS: We validate the prognosis value of the Ki67 rate in small size node negative breast cancer. We conclude that Ki67 is a potential cost-effective decision marker for adjuvant therapy in early-stage HG2, pT1-pT2, pN0, breast cancers.