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.

Simultaneous Symmetry Procedure in Patients Undergoing Oncoplastic Breast-Conserving Surgery: An Evaluation of Patient Desire and Revision Rates.

INTRODUCTION: In the era of oncoplastic breast conserving-surgery (OBCS), cosmetic outcomes and the desire for symmetry have become essential elements of the surgical management of breast cancer (BC). The timing of contralateral symmetry procedures remains a controversial topic. Simultaneous symmetry procedures (SSP) in OBCS have not been routinely offered due to the perceived risk of delayed asymmetry, potentially increasing the need for delayed cosmetic revision. This study evaluates the rate of revision after SSP in patients undergoing OBCS. METHODS: We reviewed our institutional prospectively maintained database identifying all BC patients treated surgically since our introduction of oncoplastic surgery in 2018. We routinely offer SSP when appropriate. Descriptive statistics evaluated oncoplastic surgical techniques, SSP offerings and procedures, perioperative complications, and revision rates after treatment completion. RESULTS: Between 2018 and 2022, 485 breast cancer patients underwent partial mastectomy, and 396 (82%) underwent OBCS. Of the 313 patients offered SSP, 272 (87%) accepted. The margin reexcision rate of this cohort was 20%. Of the 272 patients with SSP, 152 (56%) underwent intraoperative radiation therapy (IORT), and 105 (39%) had adjuvant external beam radiation therapy. Three patients (1%) experienced complications involving the symmetry side. No patients with complications experienced a delay in adjuvant therapies or requested cosmetic revisions. Three patients (1%) desired surgical revisions due to asymmetry. CONCLUSIONS: Symmetry procedures at the time of OBCS are widely accepted by patients and rarely require delayed cosmetic revision. Simultaneous symmetry procedures should be routinely discussed with patients during the surgical planning of OBCS.

A Look at the Other Side: High-Risk Lesions and Occult Contralateral Malignancy in Symmetry Procedures for Patients Undergoing Oncoplastic Breast-Conserving Surgery.

BACKGROUND: The incidence of occult breast cancer among patients undergoing reduction mammoplasty or risk-reducing mastectomies ranges from 1% to approximately 10%, respectively. Identification of incidental cancer often mandates subsequent mastectomy due to ambiguous margins. This study aimed to determine the incidence of contralateral malignancy among patients undergoing oncoplastic breast-conserving surgery (OBCS) with concurrent symmetry procedures. METHODS: The authors reviewed their prospectively maintained institutional database of patients with unilateral breast cancer who underwent OBCS. Patients who underwent excisional biopsy on the contralateral breast were analyzed separately. Patient demographics, pathologic features, and subsequent disease management were evaluated. RESULTS: Between March 2018 and July 2022, 289 patients underwent OBCS with a symmetry procedure, and 100 patients yielded contralateral breast tissue specimens. For 14 patients, a planned excisional biopsy was performed with their symmetry procedure, and five lesions (36%) were found to be malignant. Of the remaining 86 patients, 92% underwent preoperative breast magnetic resonance imaging (MRI). Four patients (4.7%) had occult malignancies identified on the contralateral breast pathology; three patients with ductal carcinoma in situ and one patient with invasive lobular carcinoma. Three patients had undergone preoperative MRI without suspicious findings. No patients required mastectomy for treatment of the contralateral breast cancer. CONCLUSION: The incidence of occult malignancy among OBCS symmetry procedures approaches 5%. The final pathology of excisional biopsies had a higher upgrade rate than previously reported. All identified malignancies were early-stage disease. The higher incidence of occult breast cancer in this population warrants the routine orientation of all specimens, which allows patients with incidental early-stage cancer the option of breast preservation.

Impact of Locoregional Treatment on Survival in Young Patients with Early-Stage Breast Cancer undergoing Upfront Surgery.

BACKGROUND: Randomized, controlled trials comparing breast-conserving therapy (BCT) with mastectomy have demonstrated equivalent overall survival (OS), but recent observational studies have shown improved OS in patients undergoing BCT. These studies provide limited data on young patients who are traditionally offered mastectomy due to perceived higher disease risk. This study examines the OS in a contemporary series of young women with breast cancer undergoing upfront BCT compared with mastectomy. METHODS: Women ≤40 years old with primary invasive T1-T2, N0-N1 breast cancer were identified from the National Cancer Database between 2006 and 2016. Patient cohorts were based according to locoregional treatment: BCT, mastectomy alone (Mx), and mastectomy with radiotherapy (Mx/RT). Kaplan-Meier method followed by Cox proportional-hazards regression with inverse probability of treatment weighting (IPTW) were performed to account for treatment selection bias effects in OS. RESULTS: A total of 15,611 patients met the study criteria; 9,509 patients (60.9%) had BCT, 4,020 (25.8%) had Mx/RT, and 2,082 (13.3%) had Mx alone. The median follow-up was 4.6 years (interquartile range [IQR] 3.0-6.4). After IPTW-adjustment, the 5-year OS was similar for BCT (95%), Mx (95%), and Mx/RT (94%), and there was no significant difference in OS in Mx (hazard ratio [HR] = 1.16, 95% confidence interval [CI] 0.90-1.51) and Mx/RT (HR = 1.08, 95% CI 0.88-1.34) compared with BCT. Mx/RT was associated with decreased survival in patients with pT2N0 (HR = 1.78, 95% CI 1.12-2.84). CONCLUSIONS: Among young patients with early-stage breast cancer, overall survival was equivalent regardless of surgical approach. Breast-conserving therapy remains a safe option in young women despite the clinical tendency to offer upfront mastectomy in young patients.

Is the 21-Gene Recurrence Score on Core Needle Biopsy Equivalent to Surgical Specimen in Early-Stage Breast Cancer? A Comparison of Gene Expression Between Paired Core Needle Biopsy and Surgical Specimens.

BACKGROUND: Molecular testing on surgical specimens predicts disease recurrence and benefit of adjuvant chemotherapy in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer (EBC). Testing on core biopsies has become common practice despite limited evidence of concordance between core/surgical samples. In this study, we compared the gene expression of the 21 genes and the recurrence score (RS) between paired core/surgical specimens. METHODS: Eighty patients with HR+/HER2- EBC were evaluated from two publicly available gene expression datasets (GSE73235, GSE76728) with paired core/surgical specimens without neoadjuvant systemic therapy. The expression of the 21 genes was compared in paired samples. A microarray-based RS was calculated and a value ≥ 26 was defined as high-RS. The concordance rate and kappa statistic were used to evaluate the agreement between the RS of paired samples. RESULTS: Overall, there was no significant difference and a high correlation in the gene expression levels of the 21 genes between paired samples. However, CD68 and RPLP0 in GSE73235, AURKA, BAG1, and TFRC in GSE76728, and MYLBL2 and ACTB in both datasets exhibited weak to moderate correlation (r < 0.5). There was a high correlation of the microarray-based RS between paired samples in GSE76728 (r = 0.91, 95% confidence interval [CI] 0.81-0.96) and GSE73235 (r = 0.82, 95% CI 0.71-0.89). There were no changes in RS category in GSE76728, whereas 82% of patients remained in the same RS category in GSE73235 (κ = 0.64). CONCLUSIONS: Gene expression levels of the 21-gene RS showed a high correlation between paired specimens. Potential sampling and biological variability on a set of genes need to be considered to better estimate the RS from core needle biopsy.

Delay in surgery is associated with axillary upstaging of clinically node negative breast cancer patients.

BACKGROUND AND OBJECTIVES: Most breast cancer (BC) patients present with early disease and clinically negative lymph nodes (cN0). Timing of surgery has not been standardized. We hypothesized that surgical delay results in an increased likelihood of nodal metastasis. METHODS: Patients diagnosed with cN0 BC undergoing surgery with sentinel lymph node biopsy as initial therapy between 2006 and 2014 were identified in the NCDB and divided into four groups based on time intervals between diagnosis and surgery (<4 weeks, 4-8 weeks, 8-12 weeks, and >12 weeks). Regression analysis evaluated the independent impact of surgical timing on axillary upstaging and survival. RESULTS: Of 355,443 patients with cN0 BC, 39.6% had surgery within 4 weeks and 5.4% more than 12 weeks from diagnosis. After controlling for relevant factors, a month delay in surgery was associated with an increased likelihood of nodal positivity (odds ratio: 1.04; 95% confidence interval [CI]: 1.04-1.05; p < .001) and decreased overall survival (hazard ratio: 1.03; 95% CI: 1.02-1.04; p < .001). When compared to patients who underwent surgery less than 4 weeks from diagnosis, the absolute increase in nodal positivity and relative risks were 5.3% (95% CI: 0.047-0.059) and 1.34 (95% CI: 1.30-1.38), respectively, in the more than 12 weeks group. CONCLUSIONS: Delay in BC surgery in cN0 patients was associated with an increased likelihood of axillary upstaging and decreased survival.

Oncoplastic Breast-Conserving Surgery: Can We Reduce Rates of Mastectomy and Chemotherapy Use in Patients with Traditional Indications for Mastectomy?

INTRODUCTION: Traditional indications for mastectomy include multiple ipsilateral lesions and/or disease spanning ≥ 5 cm. Neoadjuvant chemotherapy increases breast conservation but does not improve survival. We hypothesized that oncoplastic breast-conserving surgery (OPS) may allow for breast conservation while providing full staging and tumor profiling information to guide systemic therapy decisions, thereby permitting more judicious chemotherapy use. METHODS: This was an observational cohort of patients with invasive breast cancer with multiple lesions and/or disease spanning ≥ 5 cm who underwent OPS from 2012 to 2018. Clinicopathologic features, mastectomy rate, chemotherapy use, and recurrence were evaluated. RESULTS: Overall, 100 patients were identified. Average disease span was 62.8 ± 20.1 mm, with an average of 2.9 lesions (range 1-13). 'No ink on tumor' was achieved at the index operation in 80 patients; 13 patients underwent completion mastectomy to achieve adequate margins. Eighty-one patients completed radiation therapy. Breast conservation was possible in 50/58 (86%) patients who did not receive chemotherapy. Forty-two patients received chemotherapy (8 neoadjuvant, 34 adjuvant), of whom 37 (88%) achieved breast conservation. Twenty-six patients with high-risk features received adjuvant chemotherapy. Oncotype DX testing demonstrated the need for chemotherapy in an additional eight patients. After a median follow-up of 40 months, four patients had a local recurrence, including two who declined radiation therapy. CONCLUSIONS: OPS can facilitate breast conservation in most patients with traditional indications for mastectomy. Additionally, OPS may reduce unnecessary chemotherapy, especially in patients who qualify for Oncotype DX testing. Further study evaluating long-term oncologic and cosmetic outcomes is warranted.

Oncoplastic breast-conserving therapy and intraoperative radiotherapy for management of carcinoma in situ of the breast: A single-center experience.

Intraoperative radiation therapy (IORT) has been shown to reduce local recurrence rates among women with early-stage invasive ductal carcinoma, but data regarding its use among women with in situ carcinoma are limited. In this single-institution study, 50 women with in situ carcinoma were treated with oncoplastic breast-conserving surgery (OPS) and single-dose IORT. All 50 patients had "no tumor on ink," but 9 (16%) had margins < 2 mm and required additional therapy. No local recurrences were observed after a median follow-up of 46 months. Single-dose IORT is an efficacious treatment for well-selected patients with DCIS.

Evaluating Need for Additional Imaging and Biopsy After Oncoplastic Breast-Conserving Surgery.

INTRODUCTION: Breast-conserving therapy (BCT) using oncoplastic surgery (OPS) allows for larger resections and improved aesthetics though volume redistribution and tissue rearrangement. Data regarding the impact of OPS on surveillance imaging and need for additional biopsies are limited. METHODS: This observational cohort underwent BCT at a single institution from 2009 to 2018; standard breast-conserving surgery (BCS) was the predominant approach until OPS was introduced in 2012. Rates of imaging beyond standard diagnostic views, as well as rates of biopsy following both approaches, are reported. RESULTS: A total of 422 consecutive patients were identified. The OPS group comprised 205 patients and the BCS group included 217 patients. There was no difference in need for additional imaging between groups (BCS: 58 patients [26.7%] vs. OPS: 53 patients [25.9%]; p = 0.91). When additional imaging was required, it was on the ipsilateral side in 35 (60.3%) BCS patients compared with 24 (45.3%) OPS patients (p = 0.21). The need for biopsy was higher in the BCS group (BCS: 41 patients [18.9%] with 47 total biopsies vs. OPS: 20 patients [9.3%] with 22 total biopsies; p < 0.01). Benign findings on biopsy were similar between groups (BCS: 18 [38.3%] vs. OPS: 11 [50.0%]; p = 0.66). CONCLUSIONS: OPS was not associated with an increased need for additional imaging compared with BCS. Concern regarding challenges with follow-up imaging should not impact the decision to offer OPS. Further study and longer-term follow-up is warranted to understand the trends in need for additional imaging, biopsy, and additional procedures following OPS.

Intraoperative radiation therapy in early-stage breast cancer: Presence of lobular features is not associated with increased rate of requiring additional therapy.

BACKGROUND: There is a paucity of data regarding the application of IORT to the treatment of carcinomas with lobular features. METHODS: This study includes women with invasive breast cancer who underwent breast conservation in combination with IORT from February 2011 to October 2016. Patients whose final pathology did not satisfy inclusion criteria or had inadequate margins were recommended to undergo additional therapy (AT) with WBRT as well as re-excision of inadequate margins. RESULTS: 243 invasive breast cancers were treated with IORT. The lobular features (LF) group comprised 62 patients and the invasive ductal carcinoma (IDCA) group consisted of 172 patients. Rate of AT was similar between groups (LF 19 patients, 30.6%, vs IDCA 56 patients, 32.6%, p = 0.87) groups. Lobular histology was not associated with a need for AT. Local recurrence rate for the cohort was 1.2% with a median follow up of 46 months. There was no difference in recurrence or survival after 46 months of follow-up. CONCLUSIONS: IORT is an effective treatment option for well-selected patients with early breast cancer and can be considered for patients with lobular histology.

Oncoplastic Central Partial Mastectomy and Neoareolar Reduction Mammoplasty with Immediate Nipple Reconstruction: An Initial Report of a Novel Option for Breast Conservation in Patients with Subareolar Tumors.

BACKGROUND: Breast-conserving therapy (BCT) has been associated with better quality of life and cosmetic outcomes than mastectomy. However, subareolar cancers abutting the nipple-areolar complex (NAC) present a unique cosmetic and oncologic challenge. Oncoplastic central partial mastectomy and neoareolar reduction mammoplasty with immediate nipple reconstruction is a novel technique that can permit BCT for these patients. METHODS: This study enrolled consecutive patients with central tumors during 2017-2018 who underwent central partial mastectomy reconstructed with neoareolar reduction mammoplasty and immediate nipple reconstruction. Patient demographics, imaging and pathology size, margin width, mastectomy and reexcision rates, and cosmesis were evaluated. RESULTS: The study identified 23 sequential patients. The average patient age was 60.5 ± 12.3 years, and the average body mass index was 29.4 ± 5.7 kg/m2. The mean lesion size was 51.5 ± 43.0 mm on preoperative imaging, and the average disease span shown by the final pathology was 59.5 ± 45.3 mm. "No ink on tumor" was achieved for 22 patients (95.7%). In 13 patients (56.5%), the margins were inadequate for ductal carcinoma in situ (DCIS) (n = 12) or invasive cancer (n = 1). Good to excellent cosmetic results were achieved for 21 patients (95.5%). Complications occurred for six patients (26.1%), including three patients with ischemia of the reconstructed NAC. CONCLUSION: The single-stage operation described in this report can allow patients with cancers abutting the NAC to consider BCT. This technique allows patients to avoid mastectomy and to minimize the number of operations required for reconstruction while maximizing cosmetic outcomes. In the study cohort, the presence of extensive DCIS resulted in a significant need for reexcision, which could be performed successfully without compromise to cosmetic outcome.