Biological effects of intraoperative radiation therapy: histopathological changes and immunomodulation in breast cancer patients.

Introduction: Intraoperative radiation therapy (IORT) delivers a single accelerated radiation dose to the breast tumor bed during breast-conserving surgery (BCS). The synergistic biologic effects of simultaneous surgery and radiation remain unclear. This study explores the cellular and molecular changes induced by IORT in the tumor microenvironment and its impact on the immune response modulation. Methods: Patients with hormone receptor (HR)-positive/HER2-negative, ductal carcinoma in situ (DCIS), or early-stage invasive breast carcinoma undergoing BCS with margin re-excision were included. Histopathological evaluation and RNA-sequencing in the re-excision tissue were compared between patients with IORT (n=11) vs. non-IORT (n=11). Results: Squamous metaplasia with atypia was exclusively identified in IORT specimens (63.6%, p=0.004), mimicking DCIS. We then identified 1,662 differentially expressed genes (875 upregulated and 787 downregulated) between IORT and non-IORT samples. Gene ontology analyses showed that IORT was associated with the enrichment of several immune response pathways, such as inflammatory response, granulocyte activation, and T-cell activation (p<0.001). When only considering normal tissue from both cohorts, IORT was associated with intrinsic apoptotic signaling, response to gamma radiation, and positive regulation of programmed cell death (p<0.001). Using the xCell algorithm, we inferred a higher abundance of γδ T-cells, dendritic cells, and monocytes in the IORT samples. Conclusion: IORT induces histological changes, including squamous metaplasia with atypia, and elicits molecular alterations associated with immune response and intrinsic apoptotic pathways. The increased abundance of immune-related components in breast tissue exposed to IORT suggests a potential shift towards active immunogenicity, particularly immune-desert tumors like HR-positive/HER2-negative breast cancer.

Mastectomy margins for ductal carcinoma-in-situ (DCIS): 18 Years of follow-up.

BACKGROUND: In patients undergoing mastectomy for ductal carcinoma in situ (DCIS), the significance of a positive or close (<2 mm) margin and associated recurrence risk is unclear. The study sought to evaluate risk of recurrence in relation to the mastectomy surgical margin. METHODS: A single institution retrospective review of patients with DCIS who underwent mastectomy between 2000 and 2010 was performed. Patient demographics, tumor biology, margin status and adjuvant therapy were recorded. The incidence of local recurrence (LR), distant metastasis were analyzed. RESULTS: A total of 282 patients with DCIS were identified. Overall, 12.3% of patients had a pathological positive/close margin (n = 9 tumor on ink and n = 36 <2 mm). Adjuvant radiation was administered to 11 patients with a positive or close margin. At a median follow-up of 12 years, LR was 3.4% (n = 10). None of the patients with LR had a positive or close margin. Additionally, none of the patients who received radiation developed LR. CONCLUSION: Risk of recurrence after mastectomy for DCIS is low and appears to be unrelated to margin status or the use of radiation therapy.

Supervivencia de pacientes con cáncer de mama y cirugía conservadora / Survival in Patients with Breast Cancer and Conservative Surgery

Introducción: En la actualidad la cirugía conservadora, más que una opción en el tratamiento quirúrgico del cáncer de mama, es la técnica quirúrgica de elección. Objetivo: Caracterizar la supervivencia de los pacientes con cáncer de mama operados con cirugía conservadora. Métodos: Se realizó un estudio multicéntrico, retrospectivo descriptivo de corte longitudinal, en el Hospital Universitario Clínico Quirúrgico "Arnaldo Milián Castro" y el oncológico "Celestino Hernández Robau", ambos de la ciudad de Santa Clara provincia Villa Clara, en el período comprendido desde enero del 2011 hasta diciembre del 2020. Resultados: La supervivencia global de los pacientes con cáncer de mama y cirugía conservadora en aquellos que presentaron eventos (fallecidos) fue mayor en los portadores de carcinoma ductal infiltrante con 9,3 años. En el caso del estadio tumoral predominó la supervivencia en aquellos pacientes que estaban en estadios Ia y IIa con 9,8 y 9,1 años, respectivamente. Según la inmunohistoquímica, el subtipo molecular con mejor supervivencia global fue el Luminal B con 9,2 años. En cuanto al tratamiento definitivo aplicado presentaron mayor supervivencia global aquellos pacientes que recibieron esquemas de quimioterapia+ radioterapia+ hormono terapia y quimioterapia+ radioterapia con 9,4 y 8,8 años, respectivamente. Conclusiones: Existe una mayor supervivencia global en aquellos pacientes con carcinoma ductal infiltrantes (NOS), estadios tumorales Ia y IIa, con subtipo molecular Luminal B según inmunohistoquímica y con tratamientos definitivos de quimioterapia+ radioterapia+ hormonoterapia(AU)

Introduction: Nowadays, conservative surgery, rather than an option for the surgical treatment of breast cancer, is the surgical technique of choice. Objective: To characterize the survival of patients with breast cancer operated on with conservative surgery. Methods: A multicenter, retrospective, descriptive and longitudinal study was carried out at Hospital Universitario Clínico Quirúrgico "Arnaldo Milián Castro" and "Celestino Hernández Robau" oncologic hospital, both in the city of Santa Clara, Villa Clara Province, in the period from January 2011 to December 2020. Results: The overall survival of patients with breast cancer and conservative surgery in those who presented events (died) was higher in those with infiltrating ductal carcinoma, accounting for 9.3 years. In the case of tumor stage, survival was predominant in those patients with stages IA and IIA, accounting for 9.8 and 9.1 years, respectively. Concerning immunohistochemistry, the molecular subtype with the best overall survival was Luminal B, accounting for 9.2 years. Regarding the applied definitive treatment, those patients who received chemotherapy-radiotherapy-hormone therapy and chemotherapy-radiotherapy schemes presented better overall survival, accounting for 9.4 and 8.8 years, respectively. Conclusions: Overall survival is higher in patients with infiltrating ductal carcinoma (not otherwise specified), tumor stages IA and IIA, molecular subtype Luminal B according to immunohistochemistry, and definitive treatments with chemotherapy, radiotherapy, hormone therapy scheme(AU)

Expression level of miR-155, miR-15a and miR-19a in peripheral blood of ductal carcinoma breast cancer patients: Possible bioindicators for cellular inherent radiosensitivity.

Examination of cellular radiosensitivity (RS) helps prevent the adverse side-effects of radiotherapy in radioresistant tumors. We aim to study whether miRNA-155 (miR-155), miR-19a and miR-15a can predict inherent RS according to cellular RS in breast cancer (BC) patients. This study was done on the blood samples of 40 invasive ductal carcinoma (IDC) BC patients and 15 healthy women. G2 assay was performed to evaluate cellular RS. To study the expression level of these miRNAs in blood, qRT-PCR was used. The sensitivity and specificity of the studied miRNAs were assessed by the receiver operating characteristic (ROC) curve. The yield of spontaneous (SY) and radiation-induced (RIY) chromatid breaks (CBs) was significantly different between control and patient groups (p < 0.0001). A cut-off value was specified to recognize the patients with cellular RS from those without. Expression of miR-15a was significantly downregulated (p < 0.0001) in BC patients. However, miR-19a showed upregulation in the blood of BC patients. It was also found the expression level of miR-155 and miR-19a were significantly associated with frequency of CBs (FCB) (p < 0.05). ROC curve analysis manifested that the miR-15a and miR-19a differentiate BC patients and healthy women with 0.91 and 0.68 yielding an area under the ROC curve, respectively. miR-155 and miR-19a discriminate between BC patients with and without cellular RS with area under the ROC curve 0.98 and 0.68. Our findings uncovered miR-155 and miR-19a could be applied as a bioindicator to predict cellular radiosensitivity of BC patients.

Modelling a new approach for radio-ablation after resection of breast ductal carcinoma in-situ based on the BAT-90 medical device.

The majority of local recurrences, after conservative surgery of breast cancer, occurs in the same anatomical area where the tumour was originally located. For the treatment of ductal carcinoma in situ (DCIS), a new medical device, named BAT-90, (BetaGlue Technologies SpA) has been proposed. BAT-90 is based on the administration of 90Y ß-emitting microspheres, embedded in a bio-compatible matrix. In this work, the Geant4 simulation toolkit is used to simulate BAT-90 as a homogenous cylindrical 90Y layer placed in the middle of a bulk material. The activity needed to deliver a 20 Gy isodose at a given distance z from the BAT-90 layer is calculated for different device thicknesses, tumour bed sizes and for water and adipose bulk materials. A radiobiological analysis has been performed using both the Poisson and logistic Tumour Control Probability (TCP) models. A range of radiobiological parameters (α and ß), target sizes, and densities of tumour cells were considered. Increasing α values, TCP increases too, while, for a fixed α value, TCP decreases as a function of clonogenic cell density. The models predict very solid results in case of limited tumour burden while the activity/dose ratio could be further optimized in case of larger tumour beds.

Does every woman require a post-lumpectomy mammogram and ultrasound before radiotherapy when negative margins?

PURPOSE: Most studies regarding the value of post lumpectomy imaging (PLI) studies rely on mammography alone and are often focused on patients that present with suspicious microcalcifications or in situ disease. This way, its true benefit remains controversial, which explained the heterogeneity between centers. This is the first study to evaluate the role of mammography with breast and axillary ultrasound undertaken before radiotherapy in patients with conservatively managed invasive and/or in situ carcinoma with negative margins. MATERIALS AND METHODS: In this retrospective study, medical records for patients referred to our External Radiotherapy Unit between January 2018 and December 2019 were reviewed. RESULTS: A total of 1251 patients (1262 breasts) were analyzed. A total of 3.4% had suspicious findings for local residual breast disease, with 1.0% having a re-excision positive for residual malignancy. Presentation with microcalcifications alone (OR=4.854), extension of microcalcifications>3cm (OR=13.500), histologic subtype pure ductal carcinoma in situ (OR=12.348), presence of invasive carcinoma≤1mm of the pathological margins (OR=4.630), stage pTis (5.630), and absence of invasive component (OR=4.629), were associated with an increased risk for residual malignancy. Only one patient (0.1%) had nodal residual involvement. CONCLUSION: PLI detected residual local cancer in 1.0% of the patients. PLI plays an important role in the evaluation of patients undergoing breast-conserving therapy with negative margins. The major question that remains is whether it changes survival outcomes.

Breast Irradiation in Ductal Carcinoma In Situ.

There is strong and consistent evidence that whole breast irradiation after breast conserving surgery significantly decreases the risk of ipsilateral breast events, in situ or invasive, underpinning its established role in patients with ductal carcinoma in situ (DCIS). Pending publication of the full results of BIG 3-07/TROG 07.01 randomised trial, addition of tumour bed boost to whole breast irradiation is recommended in the presence of adverse clinical-pathologic features, and the use of moderately hypofractionated whole breast dose-fractionation schedules is supported. As published data supporting the use of adjuvant partial breast irradiation in patients with low-risk DCIS are limited, its off-study application should be limited to low-risk patients defined by international and national guidelines. Finally, low-risk patients may not derive clinically meaningful benefits from radiation therapy and research on molecular profiling is ongoing to improve prognostic precision and guide safe omission of radiation therapy after breast conserving surgery.

Single institute experience of intraoperative radiation therapy in early-stage breast cancer.

ABSTRACT: Intraoperative radiation therapy (IORT) is an alternative to whole breast irradiation in selected early-stage breast cancer patients. In this single institute analysis, we report the preliminary results of IORT given by Axxent Electronic Brachytherapy (eBT) system.Patients treated with lumpectomy and eBT within a minimum follow-up period of 12 months were analyzed. Eligible criteria include being over the age of 45, having unifocal invasive ductal carcinoma (IDC) or ductal carcinoma in situ <3 cm in diameter, not exhibiting lymph node involvement on preoperative images, and negative sentinel lymph node biopsy. The eBT was given by preloaded radiation plans to deliver a single fraction of 20 Gray (Gy) right after lumpectomy.From January 2016 to April 2019, a total of 103 patients were collected. There were 78 patients with IDC and 25 with ductal carcinoma in situ. At a mean follow-up time of 31.1 months (range, 14.5-54.0 months), the local control rate was 98.1%. Two IDC patients had tumor recurrences (1 local and 1 regional failure). Post-IORT radiotherapy was given to 4 patients. There were no cancer related deaths, no distant metastases, and treatment side effects greater than grade 3 documented.We report the largest single institute analysis using the eBT system in Taiwan. The low recurrence and complication rates at a 31.1 month follow-up time support the use of the eBT system in selected early-stage breast cancer patients.

5-year results of accelerated partial breast irradiation (APBI) with SBRT (stereotactic body radiation therapy) and exactrac adaptive gating (Novalis®) for very early breast cancer patients: was it all worth it?

Purpose To explore the feasibility of image-guided and respiratory-gated Stereotactic Body Radiation Therapy (SBRT) for Accelerated Partial Breast Irradiation (APBI) in patients with very early breast cancer. Material and methods Selected patients with early breast carcinoma after breast-conserving surgery were enrolled in this phase II trial. A fiducial marker was percutaneously placed close to surgical bed and five external fiducials were set on the skin. A CT scan for planning was acquired at free breathing. The treatment was planned and DVH were assessed according to international recommendations. Prescription dose was 30 Gy in five consecutive fractions of 6 Gy. A 6MV monoenergetic LINAC (linear accelerator) that combines stereoscopic X-ray imaging system and ExacTrac Adaptive Gating technique was used. PTV (planning target volume) intrafraction motion was controlled and PTV was irradiated in a selected gated area of the respiratory cycle. Shifts for a correct, gated set-up were calculated and automatically applied. Results Between April 2013 and October 2015, a total of 23 patients were included. The median tumor size was 12 mm. The mean PTV volume was 114 cc. The mean ipsilateral lung V9 Gy was 2.2% and for left-sided breast cancers, the volume of the heart receiving 1.5 Gy was 11.5%. Maximum skin dose was 30.8 Gy. Acute toxicity was grade1 in all the patients and 100% experienced excellent/good breast cosmesis outcomes. With a median follow-up of 66 months (range 8–99 months) local-relapse-free-survival reaches 100%. One patient developed a second breast cancer outside the treated quadrant after 25.1 months. Conclusion APBI with SBRT and ExacTrac Adaptive Gating System was feasible. The acute and late toxicities were almost null and cosmesis was excellent. We also found that the margins of 5 mm applied from CTV to PTV were sufficient to compensate for geometric uncertainties (AU)

A comparative study on hypofractionated whole-breast irradiation with sequential or simultaneous integrated boost on different positions after breast-conserving surgery.

This study explored the dosimetric difference between hypofractionated whole-breast irradiation (HFWBI) with sequential boost (SEB) and simultaneous integrated boost (SIB) based on supine and prone positions to identify the superior boost mode and superior position. Thirty breast cancer patients eligible for HFWBI after breast-conserving surgery were enrolled. All patients underwent 3DCT simulation scanning in both supine and prone positions. For the SEB-HFWBI plan, the dose prescribed for the planning target volume (PTV) of whole breast (WB) was 2.67 Gy per fraction with a total of 15 fractions, followed by a sequential boost of 3.2 Gy per fraction to the PTV of tumor bed (TB) in 3 fractions. For the SIB-HFWBI plan, the dose prescribed for the PTV of WB was 2.67 Gy per fraction with a total of 15 fractions, with a simultaneously integrated boost of 3.2 Gy per fraction to the PTV of TB with a total of 15 fractions. Regardless of the position, for the PTV of TB, the conformal index (CI) in the SIB-HFWBI plans was greater than those in the SEB-HFWBI plans (T = - 8.114, - 8.114; both P < 0.05). The CI for the PTV of WB increased significantly in the prone position relative to the supine position in both two plans(Z = - 3.340, - 3.501; all P < 0.05). The study suggested that prone SIB-HFWBI might be more suitable for postoperative radiotherapy after breast-conserving surgery for early-stage breast cancer patients.

Hypofractionated whole-breast radiotherapy in large breast size patients: is it really a resolved issue?

The purpose of this study was to evaluate the impact of breast size on acute and late side effects in breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). In this study we analyzed patients over 50 years with a diagnosis of early BC, candidate for Hypo-RT after conservative surgery. Acute and late skin toxicities were evaluated in accordance with the RTOG scale. Multivariable logistic analysis was performed using dosimetric/anatomical factors resulted associated with toxicity outcome in univariable analysis. Among patients treated between 2009 and 2015, 425 had at least 5 years of follow-up. At RT end, acute skin toxicity ≥ G2 and edema ≥ G2 occurred in 88 (20.7%) and 4 (0.9%) patients, respectively. The multivariable analysis showed association of skin toxicity with boost administration (p < 0.01), treated skin area (TSA) receiving more than 20 Gy (p = 0.027) and breast volume receiving 105% of the prescription dose (V105%) (p = 0.016), but not breast size. At 5 years after RT, fibrosis ≥ G1 occurred in 89 (20.9%) patients and edema ≥ G1 in 36 (8.5%) patients. Fibrosis resulted associated with breast volume ≥ 1000 cm3 (p = 0.04) and hypertension (p = 0.04). As for edema, multivariable logistic analysis showed a correlation with hypertension and logarithm of age, but not with boost administration. Breast volume had an unclear impact (p = 0.055). A recurrent association was found between acute and late toxicities and breast V105%, which is correlated with breast size. This may suggest that a more homogenous RT technique may be preferred for patients with larger breast size.

Chronic toxicity and long-term outcome in intraoperative electron radiotherapy as boost followed by whole-breast irradiation

Purpose The administration of a dose boost to the tumor bed after breast-conserving surgery has proven to reduce local recurrence. Intra-operative electron radiotherapy (IOERT) offers an alternative method to deliver a boost with several advantages, such as direct visualization of the tumor bed, less inter- and intrafraction motion and a reduction in the number of medical appointments. The objective of our study is to assess chronic toxicity and long-term outcome for our patients after IOERT boost. Material and methods Forty-six patients treated at our institution between July 2013 and June 2020 with IOERT boost during Breast-Conserving Surgery and consecutive whole breast irradiation were prospectively analyzed. A 10–12 Gy boost was prescribed to 42 patients and 4 patients received a 20 Gy boost. An analysis for overall survival, local relapse and distant progression was performed. Acute and chronic toxicity was assessed by CTCAE 4.0. Results The median age was 64.5 years (40–90). The median follow-up was 62 months (4–86). We had no local recurrences but 2 patients (4.3%) presented a distant recurrence. Mean pathological tumor size was 16 mm (6–52). 84.8% (39) of the patients had invasive ductal carcinoma. 52.2% (24) presented histological grade II. 52.2% (24) were Luminal A like, 21.7% (10) Luminal B like, 13% (6) HER2 positive, 13% (6) triple negative. No Grade 3–4 chronic toxicity was observed. Grade 1–2 fibrosis was evidenced in 13% (6) of the patients, 4.3% (2) patients presented fat necrosis, 6.5% (3) presented seroma, 4.3% (2) had localized pain, 2.2% (1) presented localized hematoma and 2.2% (1) presented localized edema. Conclusions IOERT boost in breast cancer treatment during BCS is a safe option with low chronic toxicity. The recurrence rates are comparable to published data and emphasize that IOERT as boost is an effective treatment (AU)