Adjuvant medial versus entire supraclavicular lymph node irradiation in high-risk early breast cancer (SUCLANODE): a protocol for a multicenter, randomized, open-label, phase 3 trial.

BACKGROUND: Supraclavicular nodal (SCL) irradiation is commonly used for patients with high-risk breast cancer after breast surgery. The Radiation Therapy Oncology Group (RTOG) and European Society for Radiotherapy and Oncology (ESTRO) breast contouring atlases delineate the medial part of the SCL region, while excluding the posterolateral part. However, recent studies have found that a substantial proportion of SCL failures are located in the posterolateral SCL region, outside of the RTOG/ESTRO-defined SCL target volumes. Consequently, many radiation oncologists advocate for enlarging the SCL irradiation target volume to include both the medial and posterolateral SCL regions. Nevertheless, it remains uncertain whether adding the posterolateral SCL irradiation improves survival outcomes for high-risk breast cancer patients. METHODS: The SUCLANODE trial is an open-label, multicenter, randomized, phase 3 trial comparing the efficacy and adverse events of medial SCL irradiation (M-SCLI group) and medial plus posterolateral SCL irradiation (entire SCL irradiation, E-SCLI group) in high-risk breast cancer patients who underwent breast conserving-surgery or mastectomy. Patients with pathological N2-3b disease following initial surgery, or clinical stage III or pathological N1-3b if receiving neoadjuvant systemic therapy, are eligible and randomly assigned (1:1) to M-SCLI group and E-SCLI group. Stratification is by chemotherapy sequence (neoadjuvant vs. adjuvant), T stage (T3-4 vs. T1-2), N stage (N1-2 vs. N3), and ER status (positive vs. negative). Other radiation volumes are identical in the two arms, including breast/chest wall, undissected axillary lymph node, and internal mammary node. Advanced intensity modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or tomotherapy techniques are recommended. Both hypofractionated and conventional fractionation schedules are permitted. The primary end point is invasive disease-free survival, and secondary end points included overall survival, SCL recurrence, local-regional recurrence, distance recurrence, safety outcome, and patient-reported outcomes. The target sample size is 1650 participants. DISCUSSION: The results of the SUCLANODE trial will provide high-level evidence regarding whether adding posterolateral SCL irradiation to medial SCL target volume provides survival benefit in patients with high-risk breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05059379. Registered 28 September 2021, https://www. CLINICALTRIALS: gov/ct2/show/NCT05059379 .

Impact of clinical-pathological factors on locoregional recurrence in mastectomy patients with T1-2N1 breast cancer: who can omit adjuvant radiotherapy?

PURPOSE: Postmastectomy radiation therapy (PMRT) in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs) is controversial. This study was to identify prognostic factors of locoregional control (LRC) following mastectomy with or without PMRT for patients with T1-2N1 breast cancer and to discuss the selection of patients who might omit PMRT. MATERIALS AND METHODS: Between January 2006 and December 2012, the data of 1474 postmastectomy patients staged pT1-2N1 were analyzed. PMRT was applied in 663 patients. LRC and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Cox regression model was applied in the univariate and multivariate analyses to recognize the recurrence risk factors. RESULTS: With the median follow-up duration of 93 months (range, 5-168 months), 78 patients (5.3%) failed to secure LRC and 220 patients (14.9%) experienced any recurrence. The 7.7-year LRC and DFS was 94.9% and 85.4% respectively in the entire cohort. PMRT significantly improved 7.7-year LRC from 93.4% to 96.6% (p = 0.005), but not the DFS (p = 0.335). Multivariate analysis revealed that PMRT was an independent prognostic factor of LRC (p < 0.001), meanwhile, age ≤ 40 years (p = 0.012), histological grade 3 (p = 0.004), 2-3 positive nodes (p < 0.001) and tumor size of 3-5 cm (p = 0.045) were significantly associated with decreased LRC. The 7.7-year LRC for patients with 0, 1, and 2-4 risk factors was 97.7% / 98.9% (p = 0.233), 95.3% / 98.0% (p = 0.092), and 80.3% / 94.8% (p < 0.001) in the non-PMRT and PMRT group, respectively. CONCLUSIONS: In patients with T1-2N1 breast cancer, clinical-pathological factors including young age, histological grade 3, 2-3 positive nodes, and tumor size of 3-5 cm were identified to be predictors of a poorer LRC following mastectomy. Patients with 0-1 risk factor might consider the omission of PMRT.

Adjuvant breast inversely planned intensity-modulated radiotherapy with simultaneous integrated boost for early stage breast cancer : Results from a phase II trial.

PURPOSE: To report early toxicity and 5­year clinical outcomes of adjuvant breast inversely planned intensity-modulated radiotherapy with simultaneously integrated boost (IMRT-SIB) after breast-conserving surgery for early stage breast cancer patients. PATIENTS AND METHODS: In all, 467 patients including 406 invasive breast cancer and 61 ductal carcinoma in situ (DCIS) were enrolled in a single institutional phase II trial. All patients underwent IMRT-SIB treatment to irradiate the whole breast and the tumor bed. Doses to whole breast and surgical bed were 45 and 60 Gy, respectively, delivered in 25 fractions over 5 weeks. The grade of maximum acute skin toxicity during treatment was recorded. Lung toxicity was noted within 6 months and patient-reported cosmetic outcomes were recorded at the 12 month follow-up after the end of radiotherapy. Clinical outcomes were assessed during follow-up. RESULTS: Median follow-up time was 5.46 years. Median age was 46 years old (range 22-70 years old). No patient with DCIS had a local recurrence or distant metastasis. Among 406 patients with invasive breast cancer, the unadjusted 5­year actuarial rate of locoregional control was 98.7% (95% confidence interval [CI] 97.5-100), and distant metastasis-free survival 98.7% (95% CI 97.4-100), respectively. Acute skin toxicity was recorded at grade 0-1 in 76.5% of patients, and grade 2 in 23.5% of patients. None of these patients had grade 3 or more than grade 3 skin toxicity. Grade 1 pneumonitis was found in 25.3% of patients. Assessment of patient reported cosmetic outcomes at the 12 month follow-up showed good or excellent outcome in 86.5% of cases. CONCLUSIONS: The use of inversely planned IMRT-SIB as part of breast-conserving therapy results in optimal 5­year tumor control and minor early toxicities.

The Impact of Radiotherapy on Reoperation Rates in Patients Undergoing Mastectomy and Breast Reconstruction.

OBJECTIVE: The aim of this study was to determine the impact of postmastectomy radiotherapy (PMRT) on reoperation rates in women with breast cancer undergoing mastectomy and breast reconstruction. METHODS: Between June 2001 and December 2015, 832 breast cancer patients treated with mastectomy and breast reconstruction with (n = 159) or without (n = 673) PMRT were analyzed retrospectively. Reoperations following breast reconstruction were categorized into the following three types: anticipated, unanticipated, and others. Multivariable logistic regression models were used to evaluate the impact of PMRT on overall and unanticipated reoperations according to different breast reconstruction types after adjusting for relevant covariates. RESULTS: With a median follow-up of 58.5 months, a total of 1298 operations were performed in 832 breast cancer patients. The rates of overall and unanticipated reoperations were 46.2% and 7.7%, respectively. Multivariable analysis showed that PMRT was not associated with overall reoperations in either implant-based reconstruction patients (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.43-2.37, p = 0.995) or autologous reconstruction patients (OR 0.85, 95% CI 0.52-1.40, p = 0.533); however, the impact of PMRT on unanticipated reoperations differed by reconstruction type. In patients who received implant-based reconstructions, PMRT was associated with a 3.05-fold (95% CI 1.20-7.75, p = 0.019) higher odds of unanticipated reoperations, while there was no difference in patients who underwent autologous reconstruction (OR 1.17, 95% CI 0.51-2.66, p = 0.713). Delayed reconstruction or delayed-immediate reconstructions were associated with an increased risk of both overall and unanticipated reoperations in both reconstruction cohorts. CONCLUSIONS: PMRT appears to be associated with an increased risk of unanticipated reoperations among patients receiving implant-based reconstruction, but not among those receiving autologous reconstruction. The risk of reoperation should be taken into consideration when selecting the appropriate breast reconstruction type when PMRT is planned.

The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy.

MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51. MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231, BT-549 and CAL-51 cells with IC50 values of 9.4, 17.6 and 2.1 µmol/L, respectively. Compared with irradiation-alone treatment, pretreatment with a low dose of MK-8776 (100-400 nmol/L) significantly increased irradiation-induced γH2A.X foci in the 3 TNBC cell lines, suggesting enhanced DNA damage by MK-8776, inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines. Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg, ip) 26 d after irradiation. To explore the mechanisms underlying the radio-sensitization by MK-8776, we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines. Moreover, irradiation markedly elevated the levels of Atg5, and promoted the transformation of LC3-I to LC3-II in the cells. Pretreatment with the low dose of MK-8776 suppressed these effects. The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.

Estrogen Receptor Mediates the Radiosensitivity of Triple-Negative Breast Cancer Cells.

BACKGROUND This study aimed to evaluate differences in the radiosensitivities of triple-negative breast cancer (TNBC) and luminal-type breast cancer cells and to investigate the effects of estrogen receptor (ER) expression on the biological behaviors of the cells. MATERIAL AND METHODS Colony-forming assays were performed to detect differences in radiosensitivities in breast cancer cell lines. Gene transfection technology was used to introduce the expression of ERα in TNBC cells to compare the difference in radiosensitivity between the TNBC cells and ERα transfected cells. CCK-8 assays were used to observe changes in the proliferation of TNBC cells after ERα transfection. Immunofluorescence was used to detect the number of γH2AX foci in nuclei. Flow cytometry was used to detect changes in cell cycle distribution and apoptosis. Western blotting was used to detect changes in autophagy-associated proteins. RESULTS The radioresistance of the TNBC cell line MDA-MB-231 (231 cells) was greater than that of ERα-positive luminal-type breast cancer cell line MCF-7. Moreover, 231 cell proliferation and radioresistance decreased after ERα transfection. Interestingly, ERα-transfected 231 cells showed increased double-stranded breaks and delayed repair compared with 231 cells, and ERα-transfected 231 cells showed increased G2/M phase arrest and apoptosis after irradiation compared with those in 231 cells. ERα transfection in 231 cells reduced autophagy-related protein expression, suggesting that autophagy activity decreased in 231 ER-positive cells after irradiation. CONCLUSIONS TNBC cells were more resistant to radiation than luminal-type breast cancer cells. ERα expression may have major roles in modulating breast cancer cell radiosensitivity.

Diastolic Dysfunction Occurs Early in HER2-Positive Breast Cancer Patients Treated Concurrently With Radiation Therapy and Trastuzumab.

BACKGROUND: Left ventricular ejection fraction (LVEF) is used routinely to monitor cardiac dysfunction associated with breast cancer treatment. In this study the prevalence of early left ventricular diastolic dysfunction (LVDD) and its relationship to the dose-volume of the heart irradiated were evaluated in HER2-positive breast cancer patients undergoing concurrent trastuzumab and adjuvant radiotherapy (RT). MATERIALS AND METHODS: Data from 40 breast cancer patients treated with concurrent trastuzumab and left-sided adjuvant RT between September 2011 and October 2012 were collected prospectively. For comparison, 32 patients treated with concurrent trastuzumab and right-sided adjuvant RT and 71 patients treated with left-sided RT alone were collected retrospectively. Echocardiography was obtained before RT, immediately following RT, and 3 and 6 months after RT. Doses to the heart and left ventricle (LV) were quantified. RESULTS: Prior to RT with concurrent trastuzumab, 11 of 29 (left) and 8 of 25 (right) patients with normal baseline left ventricular diastolic function (LVDF) developed LVDD. In patients receiving left-sided RT alone, 12 of 61 patients with normal baseline LVDF developed LVDD. Dmean, D15-D40, D60-D70, and V3-V10 of the LV were significantly higher in patients who developed LVDD after concurrent trastuzumab and left-sided RT. In contrast, only two patients developed grade 1 LVEF decrease after both concurrent treatment and left-sided RT alone. CONCLUSION: Changes in LVDF compared with LVEF are more sensitive for early detection of cardiotoxicity. The dose-volume of the heart contributes significantly to the risk of LVDD in patients with left-sided breast cancer treated concurrently with trastuzumab. IMPLICATIONS FOR PRACTICE: Abnormalities in diastolic function are more sensitive than changes in the left ventricular ejection fraction for detecting acute cardiotoxicity and are related to the dose-volume of the heart irradiated in patients with left-sided breast cancer receiving radiotherapy concurrently with trastuzumab. This result highlights the importance of decreasing the dose-volume of heart irradiated as a protective strategy in the treatment setting of concurrent trastuzumab and radiotherapy. Diastolic dysfunction may serve as a more sensitive tool for the early detection of cardiac damage and should be incorporated as a routine parameter in the functional monitoring of cardiotoxicity.

Clinical outcomes after post-operative radiotherapy for breast cancer patients presenting with ipsilateral supraclavicular metastasis: considerations on the cranial border of irradiation field.

BACKGROUND: Disease recurrence at lower neck adjacent to ipsilateral supraclavicular (SCV) region represents a concern in locally advanced breast cancer patients presenting with SCV metastasis at diagnosis. This study aims to report the outcomes following post-operative radical radiation therapy and discuss the reasonable cranial border of the irradiation field for N3c patients. METHODS: Between July 2016 and January 2022, a total of 268 patients were eligible for analysis. The endpoints included in-field and out-field cervical failures, local-regional recurrence-free survival (LRRFS), SCV recurrence-free survival (SRFS), distant metastasis-free survival (DMFS), relapse-free survival (RFS), and overall survival (OS). RESULTS: During a median follow-up of 37 months (range 3-89 months), 17 patients (6.3%) developed local-regional recurrence as the first recurrence event, with 13 having concomitant distant-metastasis (DM); 56 patients (20.9%) had DM alone. The 3-year rates of LRRFS, SRF, DMFS, RFS, and OS were 92.3%, 94.5%, 74.5%, 73.0%, and 90.0%, respectively. 89.2% of patients received RT with the cranial border at the top of hyoid bone, and 95.1% of patients received a boost not exceeding the level of cricoid cartilage. A total of 11 patients (4.1%) developed ipsilateral SCV failure, and 3 patients (1.1%) experienced cervical failure, including 2 in-field failures and 1 out-field failure. Neoadjuvant systemic therapy (NST) was administered to 234 patients (87.3%). In the multivariate analysis, non-ypN0, triple-negative subtype and cT4 at diagnosis were predictors of worse SRFS and RFS in NST subgroup. CONCLUSION: Our findings suggest that radical RT with cranial border of irradiation field at the hyoid bone level lead to excellent local-regional control, and out-field cervical failure was rare. The irradiation field might not extend to mastoid process.

CXCR6 expression correlates with radiotherapy response and immune context in triple-negative breast cancer-experimental studies.

BACKGROUND: The chemokine receptor CXCR6 is critical for sustained tumor control mediated by CD8+ cytotoxic T cells (CTLs) in tumors. Previous studies have shown that ionizing radiation induces an inflamed immune contexture by upregulating CXCR6. However, the clinical significance of CXCR6 expression in triple-negative breast cancer (TNBC) and its correlation with radiotherapy remains unknown. This study aimed to clarify the prognostic value of CXCR6 and its role in the breast tumor microenvironment (TME). METHODS: The messenger RNA and protein expression of CXCR6 in human TNBC and their association with survival were analyzed. The role of CXCR6 in the immune context was investigated using a combination of single-cell RNA sequencing, bulk transcriptome sequencing data, and fluorescence-based multiplex immunohistochemistry (mIHC) techniques. RESULTS: Elevated CXCR6 expression correlated with better clinical outcomes and superior response to adjuvant radiotherapy and immunotherapy in TNBC. CXCR6 fostered an immunostimulatory microenvironment characterized by upregulated cytotoxic markers. We also found that CXCR6 plays a crucial role in regulating the differentiation of CD8+ T cells and the intercellular communication of immune cell subtypes, thus shaping the TME. CONCLUSIONS: This study highlights the emerging role of CXCR6 in shaping the TME and targeting CXCR6 may be a promising strategy for improving the effectiveness of radiotherapy and immunotherapy in TNBC.

Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases: A Nonrandomized Phase 2 Trial.

Importance: The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear. Objective: To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases. Design, Setting, and Participants: This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023. Interventions: Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects. Main Outcomes and Measures: The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function. Results: A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points. Conclusions and Relevance: The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation. Trial Registration: ClinicalTrials.gov Identifier: NCT04582968.

Radiotherapy can improve the disease-free survival rate in triple-negative breast cancer patients with T1-T2 disease and one to three positive lymph nodes after mastectomy.

PURPOSE: Several studies have demonstrated poor locoregional control in patients with triple-negative breast cancer (TNBC), compared with other molecular subtypes of breast cancer. We sought to evaluate whether or not postmastectomy radiotherapy (PMRT) improves locoregional recurrence-free survival (LRFS) and disease-free survival (DFS) outcomes in TNBC patients. METHODS AND MATERIALS: Between January 2000 and July 2007, 553 TNBC patients treated with modified radical mastectomy from a single institution were analyzed retrospectively. Patients were categorized into three groups: low risk (stage T1-T2N0), intermediate risk (stage T1-T2N1), and high risk (stage T3-T4 and/or N2-N3). Cox proportional hazards models were used to evaluate the association between PMRT and LRFS and DFS times after adjusting for other clinicopathologic covariates. RESULTS: With a median follow-up of 65 months (range, 1-140 months), 51 patients (9.2%) developed locoregional recurrence and 135 patients (24.4%) experienced disease recurrence. On multivariate analysis, PMRT was associated with significantly longer LRFS and DFS times in the entire cohort. In the intermediate-risk group, PMRT was associated with a longer DFS time but not with the LRFS interval. In the high-risk group, PMRT was associated with significantly longer LRFS and DFS times. CONCLUSION: PMRT is associated with longer LRFS and DFS times in high-risk TNBC patients and a longer DFS time in intermediate-risk TNBC patients. Prospective randomized studies are needed to investigate the best locoregional treatment approaches for patients with this molecular subtype of breast cancer.

Systemic treatment after whole-brain radiotherapy may improve survival in RPA class II/III breast cancer patients with brain metastasis.

Whole brain radiotherapy (WBRT) is the most widely used treatment for brain metastasis (BM), especially for patients with multiple intracranial lesions. The purpose of this study was to examine the efficacy of systemic treatments following WBRT in breast cancer patients with BM who had different clinical characteristics, based on the classification of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) and the breast cancer-specific Graded Prognostic Assessment (Breast-GPA). One hundred and one breast cancer patients with BM treated between 2006 and 2010 were analyzed. The median interval between breast cancer diagnosis and identification of BM in the triple-negative patients was shorter than in the luminal A subtype (26 vs. 36 months, respectively; P = 0.021). Univariate analysis indicated that age at BM diagnosis, Karnofsky performance status/recursive partitioning analysis (KPS/RPA) classes, number of BMs, primary tumor control, extracranial metastases and systemic treatment following WBRT were significant prognostic factors for overall survival (OS) (P < 0.05). Multivariate analysis revealed that KPS/RPA classes and systemic treatments following WBRT remained the significant prognostic factors for OS. For RPA class I, the median survival with and without systemic treatments following WBRT was 25 and 22 months, respectively (P = 0.819), while for RPA class II/III systemic treatments significantly improved OS from 7 and 2 months to 11 and 5 months, respectively (P < 0.05). Our results suggested that triple-negative patients had a shorter interval between initial diagnosis and the development of BM than luminal A patients. Systemic treatments following WBRT improved the survival of RPA class II/III patients.

A retrospective study of adjuvant proton radiotherapy for breast cancer after lumpectomy: a comparison of conventional-dose and hypofractionated dose.

PURPOSE: This study aimed to compare the adverse reactions of conventional-dose and hypofractionated dose of proton therapy for breast cancer. MATERIALS AND METHODS: Breast cancer patients treated with proton radiotherapy in conventional-dose or hypofractionated dose were studied retrospectively. RESULT: From January 2017 to December 2019, our center treated 50 patients following lumpectomy with proton radiotherapy. According to the AJCC 8th Edition standard, there were stage I in 26 patients, stage II in 22 patients, and stage III in 2 patients. A total of 14 patients received intensity-modulated proton therapy at a dose of 50 Gy in 25 fractions, followed by a 10 Gy 4 fractionated boost to the lumpectomy cavity, while 36 received 40.05 Gy in 15 fractions, simultaneous integrated boost (SIB) 48 Gy to the lumpectomy cavity. Median follow-up time for 40.05 Gy group was 35.6 months (15-43 months). Median follow-up time for 50 Gy group was 46.8 months (36-68 months). For acute toxicity, the grade 1 and 2 radiodermatitis in conventional-dose group were 35.7% and 57.1%, respectively. In hypofractionated dose group, the grade 1 and 2 radiodermatitis were 91.7% and 8.3%, respectively. The radiodermatitis is hypofractionneted dose better than conventional-dose significantly. Grade 1 radiation-induced esophagitis in conventional-dose group and hypofractionated dose group were 85.71% and 60%, respectively. For late toxicity, no patients developed radiation-induced pneumonitis and rib fracture in conventional-dose group. Three patients presented grade 1 pneumonitis; one patient presented graded 2 pneumonitides and two patients presented rib fracture in hypofractionated dose group. One presented hypothyroidism in hypofractionated dose group. All patients were satisfied with breast shape. The one- and two-year OS and DFS for conventional-dose group were 100 and 100; 100 and 92.9%, respectively. The one- and two-year OS and DFS for hypofractionated dose group were 100 and 100; 100 and 100%, respectively. CONCLUSION: Proton radiation therapy can significantly reduce the normal tissue dose in breast cancer patients' hearts, lungs, and other organs. Hypofractionated proton therapy shortens the treatment course with mild radiation-related adverse effects, and has a better effect on addressing the acute adverse reactions than conventional proton radiotherapy.

Favorable prognosis of breast cancer brain metastases patients with limited intracranial and extracranial metastatic lesions.

BACKGROUND: Breast cancer brain metastases (BCBM) are highly heterogenous with widely differing survival. The prognosis of the oligometastatic breast cancer (BC) patients with brain metastases (BM) has not been well studied. We aimed to investigate the prognosis of BCBM patients with limited intracranial and extracranial metastatic lesions. METHODS: Four hundred and forty-five BCBM patients treated between 1st January 2008 and 31st December 2018 at our institute were included. Clinical characteristics and treatment information were obtained from patient's medical records. The updated breast Graded Prognostic Assessment (Breast GPA) was calculated. RESULTS: The median OS after diagnosis of BM were 15.9 months. Median OS for patients with GPA 0-1.0, 1.5-2, 2.5-3 and 3.5-4 were 6.9, 14.2, 21.8, 42.6 months respectively. The total number of intracranial and extracranial metastatic lesions, in addition to the Breast GPA, salvage local therapy and systemic therapy (anti-HER2 therapy, chemotherapy and endocrine therapy) were demonstrated to be associated with prognosis. One hundred and thirteen patients (25.4%) had 1-5 total metastatic lesions at BM diagnosis. Patients with 1-5 total metastatic lesions had a significantly longer median OS of 24.3 months compared to those with greater than 5 total metastatic lesions with a median OS of 12.2 months (P < 0.001; multivariate HR 0.55, 95% CI, 0.43-0.72). Among the patients with 1-5 metastatic lesions, median OS for GPA 0-1.0 was 9.8 months, compared to 22.8, 28.8 and 71.0 for GPA 1.5-2.0, 2.5-3.0 and 3.5-4.0 respectively, which is much longer than the corresponding patients with greater than 5 total metastatic lesions, with medium OS of 6.8, 11.6, 18.6 and 42.6 months respectively for GPA 0-1.0, 1.5-2.0, 2.5-3.0 and 3.5-4.0. CONCLUSIONS: The patients with 1-5 total metastatic lesions demonstrated better OS. The prognostic value of the Breast GPA and the survival benefit of salvage local therapy and continuation of systemic therapy after BM were confirmed.

The Role of Radiotherapy for Patients with Unresectable Locally Advanced Breast Cancer following Neoadjuvant Systemic Therapy.

Background: For locally advanced breast cancer (LABC) patients who remained unresectable after neoadjuvant systemic therapy (NST), radiotherapy (RT) is considered as an approach for tumor downstaging. In this study, we attempted to discuss the value of RT for patients with unresectable or progressive disease in the breast and/or regional nodes following NST. Methods: Between January 2013 and November 2020, the data for 71 patients with chemo-refractory LABC or de novo bone-only metastasis stage IV BC who received locoregional RT with or without surgical resection were retrospectively analyzed. Factors associated with tumor complete response (CR) were recognized using logistic regression. Locoregional progression-free survival (LRPFS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The Cox regression model was applied to recognize the recurrence risk factors. Results: After RT, 11 patients (15.5%) achieved total cCR. Triple-negative subtype (TNBC) was associated with a lower total cCR rate compared with other subtypes (p = 0.033). 26 patients proceeded to surgery, and the operability rate was 36.6%. 1-year LRPFS and PFS were 79.0% and 58.0%, respectively, for the entire cohort. Surgical cases had an improved 1-year LRPFS (p = 0.015), but not 1-year PFS (p = 0.057), compared with definitive RT cases. Non-any cCR was the most prominent predictor of a shorter LRPFS (p < 0.001) and PFS (p = 0.002) in the multivariate analysis. Higher TNM stage showed a trend toward a shorter LRPFS time (p = 0.058), and TNBC (p = 0.061) showed a trend toward a shorter PFS interval. Conclusions: This study demonstrated that RT was an effective tumor downstaging option for chemo-refractory LABC. For patients with favorable tumor regression, surgery following RT might bring survival benefits.

Molecular subtypes predict second breast events of ductal carcinoma in situ after breast-conserving surgery.

PURPOSE: Currently, the prognostic value of molecular subtypes in ductal carcinoma in situ (DCIS) remains unclear. In this study, we explored whether molecular subtypes could predict second breast events (SBEs) in patients after breast-conserving surgery (BCS). METHODS: From January 2008 to December 2016, 291 DCIS patients treated with BCS were retrospectively analyzed. Patients were classified into four molecular subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) overexpression, and triple-negative breast cancer (TNBC). The SBE incidence was calculated by the competing risk model and compared by Gray's test. The disease-free survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. Prognostic factors were evaluated by univariate and multivariate COX proportional hazards regression model. RESULTS: With a median follow-up of 66 months, 12 SBEs were identified. The 5-year overall SBE incidence of luminal A, luminal B, HER2 overexpression, and TNBC was 2.18%, 4.25%, 15.15%, and 0.00%, respectively. In the univariate analysis, the HER2 overexpression subtype was the predictor of overall (p = 0.005), in situ (p = 0.004), and ipsilateral SBEs (p = 0.008). Patients with endocrine therapy were less likely to develop in situ SBEs (p = 0.039). Additionally, patients with closed (<2 mm) or involved margins were related to a higher risk of contralateral SBEs (p = 0.029). In the multivariate analysis, the HER2 overexpression subtype remained of prognostic values for overall (p = 0.006), in situ (p = 0.029), and ipsilateral SBEs (p = 0.012). CONCLUSIONS: The molecular subtype, especially the HER2 overexpression subtype, was the independent prognostic factor for DCIS patients who underwent BCS.

Entire Versus Medial Supraclavicular Nodal Irradiation for Patients With High-Risk Node-Positive Breast Cancer.

PURPOSE: We aimed to examine whether elective inclusion of the posterolateral supraclavicular node (SCL) region to the standard medial SCL target volume improves SCL control and survival outcomes in patients with high-risk node-positive breast cancer undergoing regional nodal irradiation (RNI). METHODS AND MATERIALS: We retrospectively reviewed 544 consecutive women with high-risk breast cancer treated with postoperative chest wall/breast and RNI in our center from January 2015 to December 2016. High-risk features were defined as clinical or pathologic stage N2-3b disease. Patients were classified into the medial SCL irradiation (M-SCLI) group and the entire SCL irradiation (E-SCLI) group, which included both the medial and the posterolateral SCL region. SCL recurrence (SCLR), disease-free survival (DFS), and overall survival (OS) were estimated and compared. Propensity-score matching (PSM) and multivariate cox regression were used for analysis. RESULTS: The median follow-up time was 64.2 months. Before PSM, there was no significant difference in the cumulative incidence of SCLR between the 2 groups, with 5-year rates of 2.0% in the M-SCLI group and 0.6% in the E-SCLI group (P = .1). After PSM, there was also no significant difference in the cumulative incidence of SCLR (2.1% vs 0.5%; P = .2). Only 2 patients had recurrence in the posterolateral SCL region, with 1 patient in each group. Similarly, there was no significant difference in DFS and OS between the M-SCLI and E-SCLI group both before PSM (5-year rates of 78.5% vs 78.8%, P = .8; 92.2% vs 90.0%, P = .2) and after PSM (76.7% vs 77.2%, P = .8; 91.5% vs 88.4%, P = .1). Multivariate analysis demonstrated that E-SCLI was not independently prognostic for DFS and OS. CONCLUSIONS: E-SCLI does not appear to be associated with improved SCL control and survival outcomes in high-risk node-positive breast cancer. These data do not support the routine use of E-SCLI in N2-3b disease. We initiated a multicenter randomized controlled phase 3 study comparing M-SCLI and E-SCLI to further validate these results.

Symptoms Related to Brachial Plexus Neuropathy After Supraclavicular Irradiation and Boost in Breast Cancer.

PURPOSE: To evaluate the incidence of symptoms related to brachial plexus neuropathy (BPN) and the dose distribution to the brachial plexus (BP) in patients with breast cancertreated with supraclavicular (SCV) irradiation and boost. METHODS AND MATERIALS: In this study, 117 patients with initial ipsilateral supraclavicular lymph node (SLN) metastasis and 39 with recurrent SLN metastasis between 2008 and 2018 in our cancer center were retrospectively analyzed. All patients were treated with 50 Gy of SCV irradiation in 25 fractions and a boost (median dose, 10 Gy; range, 10-16 Gy) to involved nodes in the SCV area. Symptoms related to BPN (including ipsilateral arm numbness, pain, and weakness) were recorded and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. The BP was delineated on simulation computed tomography, and the dose distributions to the BP were evaluated. Meanwhile, 297 patients treated with SCV irradiation without boost during the same period were identified as a control group to compare the incidences of BPN-related symptoms and dosimetric data with patients who received an SCV boost. RESULTS: The 5-year overall survival rate was 80.3% for patients with initial SLN metastasis and 51.0% for patients with recurrent SLN metastasis. For patients who received an SCV boost, incidence rates of ipsilateral arm numbness, pain, and weakness were 23.9%, 18.3%, and 34.3%, respectively. Four patients (5.6%) developed grade 2 numbness and 3 (4.3%) developed grade 2 arm weakness. In the control group, incidence rates of arm numbness, pain, and weakness were 31.6%, 21.9%, and 36.0%, respectively. The incidence of BPN-related symptoms was not significantly different between the 2 groups. Symptoms of grade 3 were not observed in either cohort. The mean doses to the BP in patients who received boost and who did not were 56.8 and 46.8 Gy, respectively (P < .001). The maximum doses to the BP in patients who received boost and who did not were 64.5 and 53.5 Gy, respectively (P < .001). The BP volumes receiving at least 50 Gy, 60 Gy, 61 Gy, and 62 Gy were also significantly higher in the boosted group compared with the control group (P < .001). CONCLUSIONS: This study found that an SCV boost of 10 Gy did not increase the incidence of BPN-related symptoms and that the toxicity to the BP was acceptable. Comprehensive treatment including SCV irradiation and boost led to satisfactory survival outcomes in patients with breast cancer who had SLN metastasis.

Characteristics, prognosis, risk factors, and management of recently diagnosed ductal carcinoma in situ with microinvasion.

BACKGROUND: Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases and is arguably a more aggressive subtype of ductal carcinoma in situ (DCIS). Lacking studies with a large population, the survival outcomes of DCISM are still poorly understood and the treatment recommendations remain controversial. This study aims to investigate the long-term outcome of patients with DCISM, potential risk factors for their prognosis, and the difference of survival between patients treated with breast-conserving surgery plus radiotherapy (BCT + RT) and mastectomy only. METHODS: In total, 1299 patients from 2008 to 2019 with DCISM were retrospectively retrieved. Clinicopathological features were analyzed. Subgroup analysis was conducted between patients who underwent BCT + RT and mastectomy only. Univariate and multivariate analyses were performed to identify prognostic factors for survival. Differences of survival between two groups were compared using the log-rank test. RESULTS: Totally, 1286 patients had follow-up information, the median follow-up is 54.57 months, the 5-year local-regional-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were 98.6%, 97.1%, and 99.4%, respectively, two deaths were due to breast cancer. Multivariate analysis identified age <40 (p = 0.028) and close margin (≤2 mm) as independent negative prognostic factors for LRFS. No prognostic factors were identified for DMFS and OS. The 5-year LRFS, DMFS, and OS of patients who had DCIS component ≥5 cm and underwent mastectomy without adjuvant radiotherapy were 100%, 98.4%, and 98.4%, respectively. After propensity score matching (PSM), no survival difference was observed between patients treated with BCT + RT or mastectomy only. CONCLUSIONS: DCISM patients had a good survival, even those with DCIS component ≥5 cm. Patients aged <40 or with close margin (≤2 mm) had a poorer LRFS, but not DMFS or OS. BCT + RT is a feasible choice for DCISM patients.

Outcomes in Patients with pT3N0M0 Breast Cancer with and without Postmastectomy Radiotherapy.

PURPOSE: The role of adjuvant postmastectomy radiotherapy (PMRT) remains controversial for patients with pT3N0M0 breast cancer, especially when patients are treated with the updated adjuvant chemotherapy. Our study aimed to compare locoregional recurrence-free survival (LRFS), disease-free survival (DFS), and breast cancer-specific survival (BCSS) in pT3N0M0 patients with and without postmastectomy radiotherapy. PATIENTS AND METHODS: Between October 2000 and 8 September 2016, the database of the Breast Cancer Center of Shanghai yielded 114 patients with node-negative non-metastatic breast cancer larger than 5 cm. Univariate and multivariate analyses were performed to assess the risk factors for survivals. Differences between the two groups were compared using the Log rank test. RESULTS: Fifty-nine (51.8%) of the patients received adjuvant PMRT. The median follow-up was 62.3 months. Five-year LRFS was 100% in the PMRT group vs 98.1% in the non-PMRT group (P=0.17); 5-year DFS was 97.1% for the entire cohort, 98.0% for the PMRT group vs 96.2% for the non-PMRT group (P=0.18). Univariate analysis identified that family history of malignant tumors, lymphovascular invasion (LVI), or triple-negative breast cancer (TNBC) molecular subtype were associated with higher locoregional recurrence (LRR) (P<0.05). No PMRT was the only risk factor independently associated with poorer DFS (P=0.048) on multivariate analysis. No difference in BCSS was observed between the two groups. CONCLUSION: The present study demonstrated a low LRR rate and good survival for node-negative breast cancer >5 cm. Patients with family history of malignant tumors, TNBC subtype, LVI positivity, or grade 3 disease are at high risk for LRR and might benefit from PMRT.