Ultrasound-Guided Regional Anesthesia Using a Mixture of Dexamethasone, Dexmedetomidine, and 0.2% Levobupivacaine for Bilateral Breast Cancer Surgery Under a Spontaneous Breathing Opioid-Free Anesthesia: A Case Report.

Breast cancer is unfortunately the most common cancer in women, although survival rates have greatly increased in recent years. Breast surgery can be very aggressive and therefore highly painful, leading to high rates of acute postsurgical pain and chronic pain. In addition to general anesthesia (GA), ultrasound-guided regional anesthesia (RA) is sometimes performed to help reduce acute postoperative pain and consumption of opioids. Although effective, the main limitation of fascial plane blocks is that they require high volumes of local anesthetics, carrying the risk of local anesthetic systemic toxicity. In this article, we present the case of a 41-year-old woman, who refused GA and was successfully operated on for bilateral breast cancer, under a spontaneous breathing opioid-free sedation and ultrasound-guided RA, based on only 0.2% levobupivacaine with the addition of dexamethasone and dexmedetomidine as adjuvants. Despite this, postoperative analgesia lasted for more than 48 hours, and the patient did not require additional analgesia or opioids.

Patient specific quality assurance of volumetric modulated arc therapy of synchronous bilateral breast cancer.

Synchronous bilateral breast cancers (SBBC) present a considerable issue in external beam radiotherapy because of large fields size and large target volumes. Mono-isocentric volumetric modulated arc therapy (VMAT) appears as an appropriate irradiation technique for these types of tumors. The aim of this study was to demonstrate the utility of a 3D DVH pretreatment quality assurance program in VMAT of SBBC cases. Twenty SBBC patients who underwent radiation therapy in our department were retrospectively enrolled in this study. Fifteen patients were treated exclusively to the mammary glands. Five patients benefited from a dose boost on the tumor bed (60Gy). Nine patients were irradiated on the supraclavicular nodes (50Gy). This dose was delivered in 25 fractions and integrated boost was used when appropriate. Depending on the complexity of the treatment plans; 2 or 4 arcs VMAT plans were used in a mono-isocentric technique. The patient specific quality assurance (PSQA) was evaluated using COMPASS measured data, COMPASS reconstructed (CR) and COMPASS computed (CC) dose compared to treatment planning system (TPS) dose. Clinical evaluation was based on DVH metrics for target volumes and organ at risks. The maximum average dose deviation between TPS, CC, and CR was below 3%. The paired t-test between TPS, CC, and CR shows a strong agreement (p < 0.001). The 3DVH dose distribution comparison between TPS and COMPASS were also performed with good gamma score for global analysis. COMPASS was successfully evaluated as a 3DVH pretreatment system for SBBC despite the large fields size and complex target volumes. It allows the verification of the plan in 3D patient anatomy and the evaluation of dose discrepancies.

Evaluation of Cardiac Substructures Dose Sparing in Single and Dual Isocenter RapidArc™ Radiotherapy Planning for Synchronous Bilateral Breast Cancer.

Purpose This study compares the dosimetry and dose sparing of cardiac substructures in single isocenter and dual isocenter RapidArc™ (Varian Medical Systems, Palo Alto, California, United States) radiotherapy planning for synchronous bilateral breast cancer. Methodology Six synchronous bilateral breast cancer (SBBC) patients received adjuvant radiation with the prescribed dose of 40.05 Gy in 15 fractions to the planning target volume (PTV) without local lymph nodal regions. PTVs and organs at risk (OARs), including both lungs, esophagus, spinal cord, heart, and left anterior descending coronary artery (LAD), both atria and ventricles were contoured. Single isocentric RapidArc (SIRA) and dual isocentric RapidArc (DIRA) plans were made for each patient and dosimetric differences between these two techniques were evaluated. Results There was no statistically significant difference in conformity index (CI) values between SIRA and DIRA plans, with 0.9681±0.01 and 0.9721±0.01 (p=0.505), respectively. SIRA planning showed superior homogeneity with homogeneity Index (HI) values of 0.0999±0.01 compared to DIRA planning with HI values of 0.1640±0.12 (p=0.230). The mean LAD dose of SIRA was valued higher than that of DIRA planning. Lower mean doses were obtained for both lungs in SIRA plans compared to DIRA plans. Meanwhile, doses to the right atrium, left atrium, left ventricle, right ventricle, and esophagus showed no statistical significance between these two techniques, except in the spinal cord. Conclusion Both SIRA and DIRA plans have satisfactory outcomes in sparing OARs. Meanwhile, SIRA techniques have less setup time and overall machine time.

Dosimetric Comparison of Postmastectomy Radiotherapy Plans for Synchronous Bilateral Breast Cancer, Including Regional Lymph Node Irradiation.

BACKGROUND: To investigate the optimal radiotherapy plans for synchronous bilateral breast cancer (SBBC) patients receiving postmastectomy radiotherapy (PMRT), including regional lymph node irradiation (RNI). METHODS: For 10 SBBC patients who underwent bilateral mastectomy and received bilateral PMRT with RNI, 3 integrally optimized plans with a single isocenter were designed for each patient in this retrospective study: intensity-modulated radiation therapy (IMRT) with 9 fixed beams (9F-IMRT), volumetric-modulated arc therapy (VMAT) with 2 pairs of half arcs (2F-VMAT), VMAT with 2 pairs of outer tangential arcs and 1 pair of 200-degree arcs (3F-VMAT). The paired t-test (in the case of normal variables) and Friedman's test (in the case of nonnormal variables) were applied to compare the planning target volumes (PTVs) and organs at risk (OARs) values of the 3 techniques. RESULTS: The 3 techniques provided adequate target dose coverage and comparable results for PTVs. For OARs, 3F-VMAT yielded the lowest mean or median values of the left lung (15.02 ± 1.57 Gy) and right lung (14.91 ± 1.14 Gy), heart (6.19 (1.96) Gy), coronary artery (15.96 ± 5.76 Gy) and liver (8.10 ± 2.70 Gy) which were significantly different from those of 9F-IMRT and 2F-VMAT. The percentages of volume at various doses (V5, V10, V20, and V30) of 3F-VMAT plans were also lower than or comparable with those of 9F-IMRT and 2F-VMAT. The monitor units (MUs) of 3F-VMAT were 31% higher than those of 9F-IMRT and comparable with those of 2F-VMAT; however, there were time savings and halved beam-on times (BOTs) compared to 9F-IMRT. CONCLUSIONS: The 3F-VMAT plan yielded comparable target coverage compared with 9F-IMRT and 2F-VMAT, was superior in dose sparing of normal tissues and enabled shorter BOTs, improving treatment efficiency. In our research, 3F-VMAT was the optimal radiotherapy technique for SBBC patients receiving PMRT including RNI.

Cardiac dose in the treatment of synchronous bilateral breast cancer patients between three different radiotherapy techniques (VMAT, IMRT, and 3D CRT).

PURPOSE: Synchronous bilateral irradiation of both mammary glands and chest wall is a challenging task due to technical difficulties and limited evidence supporting an optimal technique to improve treatment outcomes. We studied and compared the dosimetry data of three radiotherapy techniques to select the most optimal one. METHODS: We compared three-dimensional conformal radiation treatment (3D CRT), intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) during irradiation of synchronous bilateral breast cancer in nine patients followed by examination of dose distribution to the cardiac conduction system (SA node, AV node and Bundle of His), myocardium, lungs, left anterior descending artery (LADA) and right coronary artery (RCA) . RESULTS: VMAT is the most sparing technique for SBBC treatment. Even though doses to the SA node, AV node and Bundle of His were higher with VMAT (Dmean were 3.75 ± 0.62, 2.58 ± 0.83 and 3.03 ± 1.18 Gy respectively) compared with 3D CRT (Dmean were 2.61 ± 0.66, 1.52 ± 0.38 and 1.88 ± 0.70 Gy respectively), this difference is statistically insignificant. Doses to the right and left lung (average Dmean = 12.65 ± 3.20 Gy, V20Gy = 24.12 ± 6.25%), myocardium (Dmean = 5.33 ± 1.51 Gy, V10Gy = 9.80 ± 3.83%, V20Gy = 7.19 ± 3.15%, V25Gy = 6.20 ± 2.93%), and LADA (Dmean = 10.04 ± 4.92 Gy, V20Gy = 18.17 ± 13.24% and V25Gy = 15.41 ± 12.19%) were highest with 3D CRT. The highest  Dmean in the cardiac conduction system (5.30 ± 2.23, 3.15 ± 1.61 and 3.89 ± 1.85 Gy respectively) was observed with IMRT, and a similar effect was noted in RCA (Dmean = 7.48 ± 2.11 Gy). CONCLUSION: VMAT is the optimal and satisfactory radiation therapy technique for sparing organs at risk (OARs). With VMAT, a lower Dmean value was noted in the myocardium, LADA, and lungs. The use of 3D CRT significantly increases the dose of radiation reaching the lungs, myocardium, and LADA, which can subsequently cause cardiovascular and lung complications, but not in the cardiac conduction system.

Clinicopathological features and prognosis of bilateral breast cancer: a single-center cohort study based on Chinese data.

Background: The incidence of bilateral breast cancer (BBC) is low, accounting for 5% of patients with breast cancer. This study aimed to investigate the clinicopathological features and prognosis of synchronous bilateral breast cancer (SBBC) and metachronous bilateral breast cancer (MBBC) in the Chinese population. Methods: Patients with BBC, including SBBC and MBBC, were selected from 6,162 breast cancer patients who underwent surgery at the Chinese People's Liberation Army (PLA) General Hospital between January 2007 and December 2019. Furthermore, patients with unilateral breast cancer (UBC) who underwent surgery at the same time were randomly selected at a ratio of 1:2 as the control group. Clinicopathological features and prognosis were compared between the groups. Results: In all, 123 (2.0%) patients with BBC were enrolled in this study, including 98 (1.6%) SBBC and 25 (0.4%) MBBC patients. A total of 280 patients with UBC were selected for the control group. Compared with patients with UBC, patients with SBBC were more likely to be older and have a family history of breast cancer, non-infiltrative carcinoma, lower pathological tumor-node-metastasis (pTNM) stage, and luminal A type breast cancer as their first tumor. Patients with MBBC were more likely to be postmenopausal and have hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)] negativity, a higher pTNM stage, and a triple-negative first tumor. Patients with UBC with ER/PR (-) were more likely to develop contralateral breast cancer (CBC) than those with ER/PR (+). There was no significant difference in overall survival (OS) and disease-free survival (DFS) between patients with SBBC and patients with UBC. Patients with MBBC had worse DFS than those with UBC, but OS was similar for both types of patients. Patients with MBBC <55 years at first diagnosis had significantly shorter DFS compared to those with SBBC and UBC. A multivariate Cox proportional hazards model revealed that age ≥55 years and ER/PR negativity of the first tumor were independent risk factors for OS. Independent risk factors for DFS included MBBC, age <55 years, family history of other malignant tumors, ER/PR (-), lymphovascular invasion, and N stage ≥2 of the first tumor. Conclusions: The OS and DFS of patients with SBBC and UBC were similar. The MBBC patients, especially those <55 years old at first diagnosis, had shorter DFS than patients with UBC.

Synchronous bilateral chest wall irradiation with regional nodal irradiation: A literature review of techniques and a case study.

The optimal radiotherapy technique for patients requiring both breasts or chest walls simultaneous irradiation with or without regional nodal irradiation is currently under investigation. In the last decade several publications present case reports and case series of patients treated with adjuvant radiotherapy in both breasts or chest walls for synchronous bilateral breast cancer (SBBC) with modern radiotherapy techniques. This article presents a systematic review of relevant literature as well as a case report of a SBBC patient who received bilateral chest wall radiotherapy with regional nodal irradiation at our institution with Truebeam - Edge Linear Accelerator. Solid evidence is provided that the practice of avoiding adjuvant radiotherapy in SBBC out of fear of toxicity with older radiotherapy techniques is outdated. Modern techniques can safely and effectively deliver treatment to patients requiring both sides irradiation and even in mastectomy patients in need of regional nodal irradiation.

Evaluation of the dosimetric and radiobiological parameters in four radiotherapy regimens for synchronous bilateral breast cancer.

This study is to investigate the optimal treatment option for synchronous bilateral breast cancer (SBBC) by comparing dosimetric and radiobiological parameters of intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans using single and dual isocenters. Twenty patients with SBBC without lymph node involvement were selected retrospectively. Four treatment plans were generated for each patient using the Eclipse treatment planning system (Varian Medical System, Palo Alto, CA, USA) following two delivery techniques with two isocenter conditions-IMRT using a single isocenter (IMRT_Iso1), VMAT using a single isocenter (VMAT_Iso1), IMRT using dual isocenters (IMRT_Iso2), and VMAT using dual isocenters (VMAT_Iso2). A dose of 42.56 Gy in 16 fractions was prescribed for the planning target volume (PTV). All plans were calculated using the Acuros XB algorithm and a photon optimizer for a 6-MV beam of a Vital Beam linear accelerator. PTV-related dosimetric parameters were analyzed. Further, the homogeneity index, conformity index, and conformation number were computed to evaluate plan quality. Dosimetric parameters were also measured for the organs at risk (OARs). In addition, the equivalent uniform dose corresponding to an equivalent dose related to a reference of 2 Gy per fraction, the tumor control probability, and the normal tissue complication probability were calculated based on the dose-volume histogram to investigate the radiobiological impact on PTV and OARs. IMRT_Iso1 exhibited similar target coverage and a certain degree of dosimetric improvement in OAR sparing compared to the other techniques. It also exhibited some radiobiological improvement, albeit insignificant. Although IMRT_Iso1 significantly increased monitor unit compared to VMAT_Iso1, which is the best option in terms of delivery efficiency, there was only a 22% increase in delivery time. Therefore, in conclusion, IMRT_Iso1, the complete treatment of which can be completed using a single setup, is the most effective method for treating SBBC.

Molecular Imaging Reveals a High Degree of Cross-Seeding of Spontaneous Metastases in a Novel Mouse Model of Synchronous Bilateral Breast Cancer.

PURPOSE: Synchronous bilateral breast cancer (SBBC) patients present with cancer in both breasts at the time of diagnosis or within a short time interval. They show higher rates of metastasis and lower overall survival compared to women with unilateral breast cancer. Here we established the first preclinical SBBC model and used molecular imaging to visualize the patterns of metastasis from each primary tumor. PROCEDURES: We engineered human breast cancer cells to express either Akaluc or Antares2 for bioluminescence imaging (BLI) and tdTomato or zsGreen for ex vivo fluorescence microscopy. Both cell populations were implanted into contralateral mammary fat pads of mice (n=10), and dual-BLI was performed weekly for up to day 29 (n=3), 38 (n=4), or 42 (n=3). Primary tumors and lungs were fixed, and ex vivo fluorescence microscopy was used to analyze the cellular makeup of micrometastases. RESULTS: Signal from both Antares2 and Akaluc was first detected in the lungs on day 28 and was present in 9 of 10 mice at endpoint. Ex vivo fluorescence microscopy of the lungs revealed that for mice sacrificed on day 38, a significant percentage of micrometastases were composed of cancer cells from both primary tumors (mean 37%; range 27 to 45%), while two mice sacrificed on day 42 showed percentages of 51% and 70%. CONCLUSIONS: A high degree of metastatic cross-seeding of cancer cells derived from bilateral tumors may contribute to faster metastatic growth and intratumoral heterogeneity. We posit that our work will help understand treatment resistance and optimal planning of SBBC treatment.

Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes

Background and purpose Synchronous bilateral breast cancer (SBBC) accounts for 1–3.5% of breast cancer patients. The aim of this study was to evaluate dosimetric issues, clinical outcomes, and acute toxicities for SBBC patients receiving synchronous bilateral hypofractionated radiotherapy (SBHRT) and to compare them with patients treated with synchronous bilateral normofractionated RT schedule (SBNRT). Materials and methods From April 2016 to March 2020, 39 SBBC patients were referred to our institution. Patients were divided according to their prescription dose: Group A: 50 Gy/25fx (fractions), B: 60–64 Gy/25fx, C: 40.05 Gy/15fx; D: 48 Gy/15fx. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE)v.5.0. Results 34 patients were finally evaluated. Median follow-up was 24 months for NF schedule and 9 months for HF schedule. In the HF schedule, no acute side-effects > G2 were observed and no dermatitis was reported in 6th month´s assessments. 95% of patients have no evidence of disease and only 1 patient presented local relapse in the first mammography after RT. No distant failures or deaths were observed. Regarding dosimetric issues, the inter-patient average Dmean for the heart was: Group A: 5.0 Gy (4.6–5.5), Group B: 4.4 Gy (4.1–5.4), Group C: 4.8 Gy (4.5–5.1) and Group D: 5.3 Gy (4.4–5.6). For the lungs, the inter-patient average Dmean was: Group A: 10.8 Gy (9.8–12.2), Group B: 11.5 Gy (11.3–12), Group C: 9.8 Gy (9.3–10.5) and Group D: 10.5 Gy (10–11.3). Conclusions This is the first study reporting the safety, feasibility, and tolerability of 40.05 Gy/15fx over 3 weeks for the treatment of SBBC patients. Further study with larger accrual is mandatory (AU)

Synchronous bilateral breast cancer treated with a 3-week hypofractionated radiotherapy schedule: clinical and dosimetric outcomes.

BACKGROUND AND PURPOSE: Synchronous bilateral breast cancer (SBBC) accounts for 1-3.5% of breast cancer patients. The aim of this study was to evaluate dosimetric issues, clinical outcomes, and acute toxicities for SBBC patients receiving synchronous bilateral hypofractionated radiotherapy (SBHRT) and to compare them with patients treated with synchronous bilateral normofractionated RT schedule (SBNRT). MATERIALS AND METHODS: From April 2016 to March 2020, 39 SBBC patients were referred to our institution. Patients were divided according to their prescription dose: Group A: 50 Gy/25fx (fractions), B: 60-64 Gy/25fx, C: 40.05 Gy/15fx; D: 48 Gy/15fx. Toxicity was evaluated using Common Terminology Criteria for Adverse Events (CTCAE)v.5.0. RESULTS: 34 patients were finally evaluated. Median follow-up was 24 months for NF schedule and 9 months for HF schedule. In the HF schedule, no acute side-effects > G2 were observed and no dermatitis was reported in 6th month´s assessments. 95% of patients have no evidence of disease and only 1 patient presented local relapse in the first mammography after RT. No distant failures or deaths were observed. Regarding dosimetric issues, the inter-patient average Dmean for the heart was: Group A: 5.0 Gy (4.6-5.5), Group B: 4.4 Gy (4.1-5.4), Group C: 4.8 Gy (4.5-5.1) and Group D: 5.3 Gy (4.4-5.6). For the lungs, the inter-patient average Dmean was: Group A: 10.8 Gy (9.8-12.2), Group B: 11.5 Gy (11.3-12), Group C: 9.8 Gy (9.3-10.5) and Group D: 10.5 Gy (10-11.3). CONCLUSIONS: This is the first study reporting the safety, feasibility, and tolerability of 40.05 Gy/15fx over 3 weeks for the treatment of SBBC patients. Further study with larger accrual is mandatory.

Synchronous bilateral breast cancer patients treated with hypofractionated bilateral breast irradiation: A dosimetric and clinical study.

BACKGROUND: Bilateral breast irradiation is technically challenging and there is limited information regarding optimal technique and outcomes. Hypofractionated Radiotherapy (HFRT) has emerged as the new standard of care in early breast cancer. However, there are concerns in using hypofractionation for bilateral breast irradiation due to larger volumes and potential toxicity. Our aim was to analyze the dosimetric data and clinical outcomes in these patients. MATERIALS AND METHODS: Patients with synchronous bilateral breast cancer (SBBC) treated with bilateral breast irradiation were analyzed. All patients received simultaneous bilateral breast with or without regional nodal irradiation using a hypofractionated schedule of 40 Gy in 15 fractions over 3 weeks with single isocenter bi-tangential field-in-field intensity-modulated radiation therapy (FIF-IMRT) technique. RESULTS: Seven patients of SBBC were treated at our institute from 2015 to 2017. All patients were postmenopausal females. Five patients underwent bilateral modified radical mastectomy; two patients underwent bilateral breast conservative surgery. All patients received systemic anthracycline-based chemotherapy. The mean cardiac dose was 3.73 ± Gy and V 25 was 3.26% ± 1.96%. V 20 of lung ranged from 23.48% ± 4.47% and the mean esophageal dose was 3.6 ± 2.00 Gy. No patient had acute toxicity higher than Grade 2. At a median follow-up of 48 months, one patient died due to systemic progression. No patient reported any late toxicity. CONCLUSION: Bilateral breast irradiation using a hypofractionated schedule with single isocenter FIF-IMRT technique is technically feasible with minimal acute toxicity and no significant late effects on early follow-up.

Synchronous bilateral breast cancer: a nationwide study on histopathology and etiology.

PURPOSE: The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. METHODS: Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. RESULTS: 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13-1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01-1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue-both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. CONCLUSION: We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

Concordance of Hormone Receptor Status and BRCA1/2 Mutation Among Women With Synchronous Bilateral Breast Cancer.

Goals: BRCA1/2 mutations are associated with bilateral breast cancer. The extent of concordance between synchronous bilateral breast cancer (SBBC) tumors with respect to hormone receptor expression and BRCA1/2 mutations is unknown. We investigated the distribution of BRCA1/2 mutations and bilateral estrogen receptor (ER) status in SBBC. Methods: A retrospective analysis was performed on 15,337 patients with primary breast cancer who underwent surgical treatment at the Fudan University Shanghai Cancer Center between 2007 and 2014. We included 163 patients with synchronous bilateral breast cancer who had germline BRCA1/2 mutations testing. BRCA1/2 pathogenic/likely pathogenic mutations and other clinicopathological characteristics were studied in further analyses. Results: Patients with SBBC developed breast cancer at an older age and had a higher rate of ER positivity than patients with UBC (p < 0.001, separately). In contrast, 14.1% of SBBC patients had carcinomas with a lobular component in either breast based on pathological reports (p < 0.001). Twelve patients had BRCA1 mutations, and 14 patients had BRCA2 mutations, while no patients had mutations in both genes. The BRCA1/2 mutation rate was higher in younger patients (23.4 vs. 11.1%, p = 0.036). SBBC patients with a family history of breast cancer or bilateral ER-negative disease had a higher frequency of BRCA1/2 mutations than the cohort without a history of these conditions. SBBC with a bilateral ER-discordant status had a very low frequency of BRCA1/2 mutations (5.6%). Patients with an ER-positive (concordant or discordant) status had better 3-year disease-free survival than patients with a concordant ER-negative status (HR = 0.324, 95% CI: 0.126-0.837, P = 0.020). However, the outcomes were similar during long-term follow-up. Pathological lymph node stage was the only prognostic factor for SBBC in both univariate and multivariate Cox analyses. Conclusions: Our study shows that Chinese women with SBBC have different characteristics from their UBC counterparts. SBBC patients with a younger age, family history of breast cancer, or bilateral ER-negative disease are more likely to have BRCA1/2 mutations. SBBC patients with a concordant ER-negative status had worse early outcomes. Our results suggest that there may be additional factors underlying the tumor biology and genetics of SBBC.

The number of FoxP3-positive tumor-infiltrating lymphocytes in patients with synchronous bilateral breast cancer.

PURPOSE: In breast cancer, FoxP3-positive tumor-infiltrating lymphocytes (FoxP3+ TILs) vary depending on lymph node status, histological grade, and subtype. All these studies have compared the numbers of FoxP3+ TILs among different hosts, but recruitment of FoxP3+ TILs might depend on each individual's immune environment and each tumor's biological characteristics. In the present study, FoxP3+ TIL numbers were investigated in patients with synchronous bilateral breast cancer (SBBC) to determine the factors that affect FoxP3+ TIL recruitment in the same anti-tumor immune environment. METHODS: Patients diagnosed with SBBC who underwent curative surgery at two institutions were enrolled in this study. Patients who underwent primary systemic therapy or who were diagnosed with ductal carcinoma in situ or who had distant metastases at diagnosis were excluded. The average numbers of Foxp3+ TILs were determined from the scores of five high-power microscopic fields (HPF). The associations between Foxp3+ TIL numbers and the clinicopathological features of bilateral breasts in a single individual were examined. RESULTS: Nuclear grade (NG) (p = 0.007) and subtype (p = 0.03), but not size (p = 0.18) and axillary lymph node (p = 0.23) were significantly associated with increase of FoxP3 + TIL numbers by univariate analysis. Further, only NG was a statistically significant clinicopathological factor for change in the number of FoxP3+ TILs by multivariate analysis (p = 0.046) CONCLUSIONS: There was no relationship between FoxP3+ TIL numbers and cancer progression as reflected in tumor size and axillary lymph node in patients with SBBC. Aggressive biological factors, especially high NG, were significantly related to enhanced recruitment of FoxP3+ TILs.

Evaluation of fixed-jaw IMRT and tangential partial-VMAT radiotherapy plans for synchronous bilateral breast cancer irradiation based on a dosimetric study.

PURPOSE: To investigate the fixed-jaw intensity-modulated radiotherapy (F-IMRT) and tangential partial volumetric modulated arc therapy (tP-VMAT) treatment plans for synchronous bilateral breast cancer (SBBC). MATERIALS AND METHOD: Twelve SBBC patients with pTis-2N0M0 stages who underwent whole-breast irradiation after breast-conserving surgery were planned with F-IMRT and tP-VMAT techniques prescribing 42.56 Gy (2.66 Gy*16f) to the breast. The F-IMRT used 8-12 jaw-fixed tangential fields with single (sF-IMRT) or two (F-IMRT) isocenters located under the sternum or in the center of the left and right planning target volumes (PTVs), and tP-VMAT used 4 tangential partial arcs with two isocenters located in the center of the left and right PTVs. Plan evaluation was based on dose-volume histogram (DVH) analysis. Dosimetric parameters were calculated to evaluate plan quality; total monitor units (MUs), and the gamma analysis for patient-specific quality assurance (QA) were also evaluated. RESULTS: For PTVs, the three plans had similar Dmean and conformity index (CI) values. F-IMRT showed a slightly better target coverage according to the V100% values and demonstrated an obvious reduction in V105% and Dmax compared with the values observed for sF-IMRT and tP-VMAT. Compared with tP-VMAT, sF-IMRT was slightly better in terms of V100% , V105% and Dmax . In addition, F-IMRT achieved the best homogeneity index (HI) values for PTVs. Concerning healthy tissue, tP-VMAT had an advantage in minimizing the high dose volume. The MUs of the tP-VMAT plan were decreased approximately 1.45 and 1 times compared with the sF-IMRT and F-IMRT plans, respectively, and all plans passed QA. For the lungs, heart and liver, F-IMRT achieved the smallest values in terms of Dmean and showed a significant difference compared with tP-VMAT. Simultaneously, sF-IMRT was also superior to tP-VMAT. For the coronary artery, tP-VMAT achieved the lowest Dmean , while the value for F-IMRT was 2.24% lower compared with sF-IMRT. For all organs at risk (OARs), tP-VMAT was superior at the high dose level. In contrast, sF-IMRT and F-IMRT were obviously superior at the low dose level. The sF-IMRT and F-IMRT plans showed consistent trends. CONCLUSION: All treatment plans for the provided techniques were of high quality and feasible for SBBC patients. However, we recommend F-IMRT with a single isocenter as a priority technique because of the tremendous advantage of local hot spot control in PTVs and the reduced dose to OARs at low dose levels. When the irradiated dose to the lungs and heart exceed the clinical restriction, two isocenter F-IMRT can be used to maximize OAR sparing. Additionally, tP-VMAT can be adopted for improving cold spots in PTVs or high-dose exposure to normal tissue when the interval between PTVs is narrow.

Skin and lung toxicity in synchronous bilateral breast cancer treated with volumetric-modulated arc radiotherapy: a mono-institutional experience.

PURPOSE: To evaluate acute and late skin/subcutaneous toxicities and radiation-induced lung fibrosis (RILF) in patients treated with adjuvant radiotherapy (RT) for synchronous bilateral breast cancers (SBBC), after conservative surgery. METHODS/PATIENTS: Twenty-five patients were treated with volumetric-modulated arc therapy (VMAT/RapidArc®) on both breasts, and checked clinically for detecting RT toxicities during and after treatment. A high-resolution computed tomography (HRCT) was performed, for detecting RILF during follow-up. RESULTS: We registered acute Grade-1 skin toxicity in 18 patients (72%), while six patients (24%) experienced Grade-2 toxicity. No breath symptoms were reported during and after RT. Late Grade-1 subcutaneous toxicity and late Grade-2 skin toxicity were registered in four patients (16%) and one patient (4%), respectively, at a mean follow-up of 36 months. Grade-1 RILF was detected in six patients (30%). The median volume of fibrosis area was 6.5 cc (range 1.3-21.5 cc). The partial volumes receiving a specified dose (V20, V30, V40, and V50) in patients who developed lung fibrosis were significantly bigger than who did not (p < 0.01). We showed that the mean volume of the tumour boost of patients who developed fibrosis (77.7 cc) was not significantly different from the other patients (90.8 cc) (p = 0.5). CONCLUSION: The clinical impact of this technique is favourable, and this is the first clinical study showing RILF by HRCT in a setting of SBBC. Further study with larger accrual is mandatory.

Heart and Cardiac Substructure Dose Sparing in Synchronous Bilateral Breast Radiotherapy: A Dosimetric Study of Proton and Photon Radiation Therapy.

Background: Synchronous bilateral breast cancer (SBBC) is rare. The purpose of this study was to compare the dosimetric differences in intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), helical tomotherapy (HT), and intensity-modulated proton therapy (IMPT) to find an optimal radiotherapy technique for bilateral breast cancer radiotherapy. Methods: For 11 patients who received synchronous bilateral whole-breast irradiation without local lymph nodal regions, six plans were designed for each patient: IMRT with a single isocenter (IMRT-ISO1), IMRT with two isocenters (IMRT-ISO2), VMAT with a single isocenter (VMAT-ISO1), VMAT with two isocenters (VMAT-ISO2), HT, and IMPT. The differences between the single- and dual-isocentric plans for IMRT and VMAT were compared, and the plan with the better quality was selected for further dosimetric comparisons with IMPT and HT. The plan aimed for a target coverage of at least 95% with the prescription dose of 50 Gy [relative biological effectiveness (RBE)] while minimizing the dose of organs at risk (OARs). Results: IMRT-ISO1 and VMAT-ISO2 plans were adopted for further dosimetric comparisons because of the reduced dose of the heart and/or lungs compared to IMRT-ISO2 and VMAT-ISO1 plans. The dose coverage of the planning target volume (PTV) was significantly higher in IMPT plans than that in all other plans. VMAT and IMPT plans showed the best conformity, whereas IMRT plans showed the worst conformity. Compared to IMRT and VMAT plans, IMPT and HT plans achieved significantly higher dose homogeneity. IMPT plans reduced the mean dose and low dose volume (V5, V10, and V20) of the heart, left anterior descending artery (LAD), and left ventricle (LV). In high-dose volumes of the heart and cardiac substructures, the IMPT, VMAT, and HT techniques showed similar advantages, and IMRT plans increased the values more than other techniques. IMPT plans had the maximal lung and normal tissue sparing but increased the skin dose compared to IMRT and VMAT plans. Conclusions: IMPT plans improve both the target coverage and the OARs sparing, especially for the heart, cardiac substructures (LAD and LV), lungs and normal tissue, in synchronous bilateral breast radiotherapy. VMAT and HT could be selected as suboptimal techniques for SBBC patients.

Cáncer de mama bilateral, ¿una sola enfermedad? Concordancia de receptores hormonales / Bilateral breast cancer, a single disease? Concordance of hormonal receptors

Introducción El incremento del diagnóstico de cáncer de mama en estadios tempranos conduce a un mejor pronóstico y, por ende, a una mayor expectativa de vida, situación que posibilitaría el desarrollo de un segundo tumor contralateral. Las mujeres con cáncer de mama tienen tres a cuatro veces mayor riesgo de desarrollar un cáncer en la mama contralateral. La patogénesis de la bilateralidad no está del todo clara; las correlaciones en el subtipo histológico, el grado tumoral y el estado de los Receptores Hormonales entre los dos tumores se han considerado indicativos de que se originan de una sola célula (teoría de origen monoclonal) con diseminación metastásica secundaria hacia la mama opuesta. Por otro lado, su discordancia llevaría a considerarla una lesión independiente del tumor primario (teoría de origen multiclonal). Dependiendo del tiempo de aparición entre un tumor y el otro, suelen ser de tipo sincrónico (cmbs) y metacrónico (cmbm). Objetivo Nuestro objetivo es describir las características clínico-patológicas y la concordancia de los Receptores Hormonales entre ambos tumores. Material y método Se llevó a cabo un estudio de corte transversal y retrospectivo en dos centros, el Hospital General de Agudos Dr. Ignacio Pirovano (hgaip) y Consultorio de práctica privada (pp) en el periodo comprendido entre el 1º de agosto de 2006 y el 1º de diciembre de 2014. Los datos fueron recabados de la base de datos del Registro de Cáncer de Mama (rcm) de la Sociedad Argentina de Mastología de ambas sedes. Resultados Identificamos 1.282 pacientes con cáncer de mama tratadas en hgadip (958) y pp (324) en dicho período. Encontramos 50 casos de cáncer de mama bilateral (3,9%), de los cuales 38 (2,96%) fueron de tipo metacrónico y 12 (0,94%) de tipo sincrónico. La edad media de presentación fue similar en ambos grupos (p=0,43): 52 años para el cmbm y 54 años para el cmbs. El 29% y el 41,6 % de las pacientes tenían antecedentes familiares de cáncer de mama en los cmbm y cmbs respectivamente (p=0,43). El primer tumor metacrónico fue palpable en el 71% de las pacientes y el segundo tumor metacrónico en el 7,9% (p<0,05). En cuanto a los sincrónicos, en todos los casos se presentaron como tumor palpable en una de las mamas y en un 58% como tumor no palpable en la mama contralateral. En el primer tumor metacrónico fue más utilizada la cuadrantectomía (44,7%) y el vaciamiento axilar (55,3 %); en cambio, en el segundo tumor metacrónico, se realizó la biopsia radioquirúrgica (60,5%) y el ganglio centinela (84,2%) (p<0,05). Para los sincrónicos, la cirugía más utilizada en el tumor dominante fue la mastectomía (41,7%) y la biopsia radioquirúrgica (33%) en el tumor contralateral; el ganglio centinela fue realizado en el 41,7% de las pacientes tanto en el tumor sincrónico dominante como en el contralateral. El tipo histológico predominante fue el carcinoma ductal invasor tipo nos: 57,9% en el primer tumor metacrónico, 65,8% en el segundo tumor metacrónico, 91,6% en el tumor sincrónico dominante y 41,6% en el tumor sincrónico contralateral. Se observó carcinoma ductal in situ (cdis) asociado: en el 36,8 % en el primer tumor metacrónico, en el 44,7% en el segundo tumor metacrónico, en el 25% en el tumor sincrónico dominante y en el 50% del sincrónico contralateral. El grado histológico (gh) predominante fue gh1 en el cmbm y gh3 en el cmbs. Los tratamientos adyuvantes más utilizados en el primer tumor metacrónico fueron la radioterapia en el 79%, la quimioterapia en el 68,4% y el tamoxifeno en el 60,5%; en el segundo tumor metacrónico el uso de la radioterapia fue casi similar (81,5%), disminuyó la utilización de quimioterapia adyuvante y de tamoxifeno, ambos a un 42,1%, y el uso de Inhibidores de Aromatasa se incrementó al 52,6%. El 58,3% de las pacientes con cmbs requirió radioterapia y el 75% quimioterapia adyuvante y tamoxifeno. El 86,8% de los primeros tumores metacrónicos fue positivo para re y rp, el 10,6% fue negativo para ambos y el 2,6% fue re positivo y rp negativo. En el segundo tumor metacrónico, el 92,1% fue positivo para re y rp, el 5,2% fue negativo para ambos y solo el 2,6% se presentó como re positivo y rp negativo. En el análisis de concordancia, se observaron 32 pares metacrónicos concordantes positivos para re, 2 pares metacrónicos discordantes positivo/negativo y 4 pares metacrónicos discordantes negativo/positivo. La relación fue similar para los re: 30 pares metacrónicos concordantes positivos, 3 pares metacrónicos discordantes positivo/negativo y 5 pares metacrónicos discordantes negativo/positivo. Se observó que el 58,4% de los tumores sincrónicos dominantes expresó re y rp positivos, y el resto (41,6%) fue negativo para ambos; en el tumor sincrónico contralateral, fue casi similar: el 66,7% de los casos expresó re y rp positivos y el 33,3% fue negativo para ambos. Se observaron 7 pares sincrónicos concordantes positivos para re y rp, 4 pares sincrónicos concordantes negativos para ambos y solo un par sincrónico discordante negativo/positivo. Conclusiones La gran mayoría de las pacientes fue diagnosticada con cáncer de mama bilateral como lesión subclínica en la mama contralateral por mamografía tanto en los metacrónicos como en los sincrónicos. No se ha demostrado que el riesgo disminuya a lo largo del tiempo, por lo que se destaca la importancia del seguimiento a largo plazo como pilar fundamental para la detección temprana del cbmm que probablemente tenga un impacto favorable en la supervivencia. La concordancia en la expresión de re y rp para el cmbm fue alta (79%) y para el cmbs fue aún mayor (92%), lo que podría reflejar un efecto del microambiente hormonal que influya tanto para la iniciación como para el desarrollo de estas lesiones de forma simultánea e independiente del origen único o multiclonal

Introduction The increase of the diagnosis in the early stages of breast cancer leads to a better prognosis and therefore a longer life expectancy, a situation that would allow the development of a second contralateral tumor. Women with breast cancer have three to four times greater risk of developing cancer in the contralateral breast. The pathogenesis of bilateral breast cancer is not entirely clear; correlations in the histologic subtype, tumor grade and Hormonal Receptor status between the two tumors have been considered as an indicative of single cell origin (Monoclonal origin theory) with secondary metastatic spread to the opposite breast; the discordance of those parameters would consider an independent lesion of the primary tumor (theory of multiclonal origin). They are named synchronous and metachronous depending on the time of onset. Objective Our study aims to describe the clinical-pathological characteristics and the concordance of the Hormonal Receptor status. Materials and method A cross-sectional and retrospective study was carried out at two centers, "Hospital General de Agudos Dr. Ignacio Pirovano" (hgaip) and private practice (pp) in the period from August 1, 2006 to January 1, December 2014. The data were collected from the database of "Registro de Cancer de Mama" (rcm) of the Argentine Society of Mastology (sam) from both centers. Results We identified 1,282 breast cancer patients treated in hgadip (958) and pp (324). We found 50 cases with bilateral breast cancer (cmb) (3.9%); 38 patients (2.96%) were metachronous and 12 patients (0.94%) synchronous. The mean age of presentation was similar in both groups (p = 0.43): 52 years old for cmbm and 54 in the cmbs group. The 29% and 41.6% of the patients had a breast cancer family history in the cmbm and cmbs respectively (p=0.43). The first metachronous tumor was clinically palpable in 71% of the patients and in the second one in 7.9% (p <0.05). In synchronous tumors, all cases were clinically palpable in one side of the breast and in 58% were subclinical in the contralateral side. In the first metachronous tumor, the quadrantectomy (44.7%) and the lymphadenectomy (55.3%) were more commonly used; on the other hand, in the second metachronuos tumor, the radio-surgical biopsy (60.5%) and sentinel lymph node (84.2%) were more executed (p <0.05). For the synchronous, the dominant tumor had more frequently a mastectomy (41.7%) and in the contralateral tumor the radio-surgical biopsy was executed in 33%; sentinel lymph node was performed in 41.7% in both synchronous tumors. The predominant histological type was the invasive ductal carcinoma nos type: 57.9% of the first metachronous tumor, 65.8% of the second metachronous tumor, 91.6% of the dominant synchronous tumor and 41.6% of the contralateral synchronic tumor. Ductal carcinoma in situ (dcis) was associated in 36.8% in the first metachronous tumor, 44.7% in the second metachronous tumor, 25% in the dominant synchronous tumor and 50% in the contralateral synchronic tumor. The predominant histological grade (gh) was gh1 in cmbm and gh3 in cmbs. The adjuvant treatments used for the first tumor were radiotherapy in 79%, chemotherapy in 68.4% and Tamoxifen in 60.5%. For the second metachronous tumor, the use of radiotherapy was almost similar with 81.58%, and the use of adjuvant chemotherapy and Tamoxifen decreased both at 42.11%; the use of Inhibitors of Aromatase increased to 52.6%.The 86.8% of the first metachronous tumors were er and pr positive, the 10.5% were both negative, the 2.6% were er positive and pr negative. In the second metachronous tumor, the 92.1% were er and pr positive, 5.2% were both negative and 2.6% were er positive and pr negative. In the concordance analysis, we observed 32 concordant metachronous pairs of er positive, 2 discordant metachronous pairs of positive / negative and 4 discordant metachronous pairs of negative / positive. We had similar results for pr, with 30 concordant metachronous positive pairs, 3 discordant metachronous pairs of positive / negative and 5 discordant metachronous pairs of negative / positive. The 58.4% of the dominant synchronous tumors expressed er and pr positive and in the rest (41.6%) were both negative. In the contralateral synchronous tumor it was observed that 66.7% of the cases expressed er and pr positive and 33.3% were negative for both. We found 7 concordant synchronous pairs of er and pr positive, 4 concordant synchronous pairs negative for both and only 1discordant synchronous pair negative / positive Conclusions In a big amount of the patients, the contralateral breast cancer was diagnosed as a subclinical lesion by mammography in the metachronous and synchronous tumors. It has not been demonstrated that the risk decreases over the time, which highlights the importance of long-term follow-up for early detection of cmbm that probably has more favorable impact on survival. The concordance of er and pr expression for cmbm was high (79%) and for cmbs was even higher (92%), that may reflect a particular hormonal environment effect that influences both initiation and development of these lesions simultaneously and independently of single or multiclonal origin

Radiation therapy of synchronous bilateral breast carcinoma (SBBC) using multiple techniques.

The purpose of this study was to establish intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) treatment plans for synchronous bilateral breast cancer (SBBC) and to compare those plans with the previous treatment plans using 3D conformal radiation therapy (3DCRT). The differences among the treatments were also statistically compared regarding dosimetry distribution and treatment efficiency. The research was conducted with 10 SBBC patients. The study established IMRT (12 fields with a single isocenter) and VMAT (2 partial arcs with a single isocenter) treatment plans for SBBC patients and then compared those plans with 3DCRT (8 fields with multiple isocenters). The plans were evaluated based on a dose-volume histogram analysis. For planning target volumes (PTVs), the mean doses and the values of V95%, V105%, conformity index, and homogeneity index were reported. For the organs at risk, the analysis included the mean dose, maximum dose, and VXGy, depending on the organs (lungs, heart, and liver). To objectively evaluate the efficiency of the treatment plans, each plan's beam times, treatment times (including set-up time), and monitor units were compared. Tukey test and one-way analysis of variance were used to compare the PTV and organs at risk values of the 3 techniques. Additionally, the independent-samples t-test was used to compare the 2 techniques (IMRT and VMAT) based on the values of Rt. PTV and Lt. PTV (p < 0.05). For PTV dose distribution, IMRT showed increases of approximately 1.2% in Dmean and of approximately 5.7% in V95% dose distribution compared with 3DCRT. In comparison to VMAT, 3DCRT showed about 3.0% higher dose distribution in Dmean and V95%. IMRT was the best in terms of conformity index and homogeneity index (p < 0.05), whereas 3DCRT and VMAT did not significantly differ from each other. In terms of dose distribution on lungs, heart, and liver, the percentage of volume at high doses such as V30Gy and V40Gy was approximately 70% lower for IMRT and approximately 40% lower for VMAT than for 3DCRT. For distribution volumes of low doses such as V5% and V10%, that for 3DCRT was approximately 60% smaller than for IMRT and approximately 70% smaller than for VMAT. Comparison between IMRT and VMAT showed that the IMRT was superior in all distribution factors. VMAT showed better treatment efficiency than 3DCRT or IMRT. Among the SBBC radiotherapy treatment plans, IMRT was superior to 3DCRT and VMAT in terms of PTV dose distribution, whereas VMAT showed the most outstanding treatment efficiency.