Jinli Ma

Post mastectomy linac IMRT irradiation of chest wall and regional nodes: dosimetry data and acute toxicities

BackgroundConventional post-mastectomy radiation therapy is delivered with tangential fields for chest wall and separate fields for regional nodes. Although chest wall and regional nodes delineation has been discussed with RTOG contouring atlas, CT-based planning to treat chest wall and regional nodes as a whole target has not been widely accepted. We herein discuss the dosimetric characteristics of a linac IMRT technique for treating chest wall and regional nodes as a whole PTV after modified radical mastectomy, and observe acute toxicities following irradiation.MethodsPatients indicated for PMRT were eligible. Chest wall and supra/infraclavicular region +/−internal mammary nodes were contoured as a whole PTV on planning CT. A simplified linac IMRT plan was designed using either integrated full beams or two segments of half beams split at caudal edge of clavicle head. DVHs were used to evaluate plans. The acute toxicities were followed up regularly.ResultsTotally, 85 patients were enrolled. Of these, 45 had left-sided lesions, and 35 received IMN irradiation. Planning designs yielded 55 integrated and 30 segmented plans, with median number of beams of 8 (6–12). The integrated and segmented plans had similar conformity (1.41±0.14 vs. 1.47±0.15, p=0.053) and homogeneity indexes (0.13±0.01 vs. 0.14±0.02, p=0.069). The percent volume of PTV receiving >110% prescription dose was <5%. As compared to segmented plans, integrated plans typically increased V5 of ipsilateral lung (p=0.005), and heart (p=0.001) in patients with left-sided lesions. Similarly, integrated plans had higher spinal cord Dmax (p=0.009), ipsilateral humeral head (p<0.001), and contralateral lung Dmean (p=0.019). During follow-up, 36 (42%) were identified to have ≥ grade 2 radiation dermatitis (RD). Of these, 35 developed moist desquamation. The median time to onset of moist desquamation was 6 (4–7) weeks from start of RT. The sites of moist desquamation were most frequently occurred in anterior axillary fold (32/35), and secondly chest wall (12/35). The difference in occurrence of ≥ grade 2 RD between integrated and segmented plans was statistically insignificant (X2=0.35, p=0.55). Only 2 were found to have grade 2 radiation pneumonitis.ConclusionsThe linac IMRT technique applied in PMRT with chest wall and regional nodes as a whole PTV was dosimetrically feasible, and the treatment was proved to be well-tolerated by most patients.

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. 36xa0months, respectively; Pxa0=xa00.021). 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) (Pxa0<xa00.05). 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 22xa0months, respectively (Pxa0=xa00.819), while for RPA class II/III systemic treatments significantly improved OS from 7 and 2xa0months to 11 and 5xa0months, respectively (Pxa0<xa00.05). 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.

HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo

Growing evidence has demonstrated that human epidermal growth factor receptor 2 (HER2) is involved in the radiation response to breast cancer. However, the underlying mechanism remains elusive. Therefore, we investigated if HER2 overexpression is associated with radiosensitivity of breast cancer. We constructed breast cancer cell lines differing in HER2 expression by transducing HER2 cDNA or short hairpin RNA against HER2. We then assessed the radiosensitivity and investigated the potential mechanism by using cell proliferation assay, cell adhesion assays, anoikis assays, colony formation assays, and western blotting analyses. We found that HER2 introduction in breast cancer cell lines MCF-7 (low HER2 expression) and MDA-MB-231 (HER2 is not expressed) promoted cell proliferation and invasion and enhanced cell adhesion and resistance to anoikis. Moreover, HER2 reduced radiosensitivity in these two cells compared with the corresponding control. The opposite results were observed when HER2 was silenced in breast cancer cell lines ZR-7530 and SK-BR-3 (both cells with high expression of HER2) using HER2 shRNA. In addition, animal experiment results showed HER2 could enhance the radioresistance of xenograft tumors. Further studies showed HER2 promoted the phosphorylation of focal adhesion kinase (Fak) and thereby up-regulated the expression of proteins associated with the epithelial-to-mesenchymal transition such as Claudin-1, ZO-1, and ZEB-1. The inhibition of Fak activity using the Fak inhibitor (PF-562281) restored the radiosensitivity in HER2-overexpressing cells. In conclusion, HER2 reduces the radiosensitivity of breast cancer by activating Fak in vitro and in vivo. Fak might be a potential target for the radiosensitization of HER2-overexpressed breast cancer.

Early cardiac toxicity following adjuvant radiotherapy of left-sided breast cancer with or without concurrent trastuzumab

Purpose To evaluate the influence of concurrent trastuzumab on the cardiotoxicity in patients receiving left-sided adjuvant radiotherapy. Materials and Methods Medical records of stage I-III left-sided breast cancer patients, including 64 receiving concurrent trastuzumab with radiotherapy and 73 receiving radiotherapy alone were retrospectively reviewed. All of the patients had normal LVEF after adjuvant chemotherapy. Information of doses volume to cardiac structures was collected. Cardiac events were assessed according to CTC 2.0. Results Median follow-up of LVEF and clinical assessment of cardiac function from the initiation of radiotherapy was 6.7 months (range 3–60.9) and 26 months (range 6.4–60.9), respectively. Grade 1 LVEF dysfunction occurred in 5 (7.8%) and 3 (4.1%) patients of the concurrent-trastuzumab and radiotherapy alone cohort, respectively. Trastuzumab was the only significant factor influencing absolute LVEF decrease in univariate analysis. In multivariate analysis of concurrent-trastuzumab cohort, IMC radiotherapy and start trastuzumab during radiotherapy were independent risk factors. For concurrent cohort, mean heart dose, as well as D10-D30, D50-D55, V5-V20 of the heart and D30-D45, D65-D75, V6-V15 of the LV were significantly higher in patients developing LVEF dysfunction. Conclusions Concurrent trastuzumab and left-sided radiotherapy is well tolerated in terms of cardiotoxicity in patients with normal baseline cardiac function after adjuvant chemotherapy. However, increases in mean dose and low–dose volume of cardiac structures are associated with a higher risk of acute LVEF dysfunction.

Intraoperative Radiotherapy Versus Whole-breast External Beam Radiotherapy in Early-stage Breast Cancer: A Systematic Review and Meta-analysis

AbstractThere has not been a clear answer about the efficacy of intraoperative radiotherapy (IORT) for women with early-stage breast cancer.The aim of this meta-analysis was to summarize the available evidence comparing the efficacy and safety of IORT with those of whole-breast external beam radiotherapy (EBRT) for women with early-stage breast cancer.MEDLINE, EMBASE, the Web of Science, and the Cochrane Library were searched up to October 2014. Two authors independently conducted the literature selection and data extraction.Studies that compared IORT with whole-breast EBRT were included in the systematic review. IORT was defined as a single dose of irradiation to the tumor bed during breast-conserving surgery rather than whole-breast irradiation.Qualities of RCTs were evaluated according to the PEDro scale. Qualities of non-RCTs were evaluated according to the Methodological Index for Non-Randomized Studies (MINORS). The risk ratios (RRs) of ipsilateral breast tumor recurrence, overall mortality, breast cancer mortality, non-breast cancer mortality, and distant metastasis were pooled using a random-effects model.Four studies with 5415 patients were included in this meta-analysis, including 2 randomized controlled trials (RCTs) and 2 non-RCTs. Ipsilateral breast tumor recurrence was significantly higher in patients with IORT compared to those with whole-breast EBRT (RR 2.83, 95% CI 1.23–6.51), but with significant heterogeneity (I2u200a=u200a58.5%, Pu200a=u200a0.065). Comparing IORT with whole-breast EBRT, the pooled RRs for overall mortality, breast cancer mortality, non-breast cancer mortality, and distant metastasis were 0.88 (95% CI: 0.66–1.17), 1.20 (95% CI: 0.77–1.86), 0.76 (95% CI: 0.44–1.31), and 0.95 (95% CI: 0.61–1.49), respectively.IORT had a significantly higher risk of ipsilateral breast tumor recurrence than whole-breast EBRT. Overall mortality did not differ significantly. IORT should be used in conjunction with the prudent selection of suitable patients. It is imperative to identify women with a low risk of local recurrence.

Isolated locoregional recurrence patterns of breast cancer after mastectomy and adjuvant systemic therapies in the contemporary era

Purpose To evaluate the recurrence patterns in a series of patients who presented with isolated locoregional recurrences (ILRRs) after mastectomy and adjuvant systemic therapies in the contemporary era. Methods A total of 235 patients who developed ILRRs between 2005 and 2013 were classified into subgroups based on nodal status, hormone receptor status, and biologic subtype. The annual frequency of recurrences, association between biologic subtype and interval to recurrence (ITR), and anatomical distribution were evaluated. Results For the entire group, recurrence peaked within the first 3 years after mastectomy, and then decreased significantly with time. Node-positive patients were observed to recur early, and a greater proportion recurred within 5 years (86.7% vs. 72.8%, χ2 = 6.83, P = 0.008) than did node-negative subgroup. Overall, the median ITR was 33.2 (range, 4.5 – 236) months. Biologic subtype specific median ITR were 43.3 (7.9 – 236.0) months for luminal A, 42.2 (6.1 – 143.3) months for luminal B, 23.8 (6.9 – 47.3) months for luminal HER2, 18.2 (6.6 – 117.5) months for HER2, and 21.8 (4.5 – 138.2) months for TNBC, and their difference was statistically significant (χ2 = 7.4, P = 0.001). Among all ILRRs, 51.5% (n = 121) were isolated to regional nodes. Conclusions We demonstrates that the time course is consistent with previous description, biologic subtype is associated with ITR, and regional nodes is the most common place for recurrences in this series of patients who developed ILRRs following mastectomy and contemporary adjuvant systemic therapies but without PMRT.

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/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.

Multibeam inverse intensity-modulated radiotherapy (IMRT) for whole breast irradiation: A single center experience in China

Purpose To present the clinical experience in our cancer center with multibeam inverse intensity-modulated radiotherapy (IMRT) for early stage breast cancer (BC) patients with whole breast irradiation (WBI). Methods We retrospectively analyzed 622 patients with Stage 0 to III BC treated from 2008 to 2011 with wide local excision and WBI, using an inverse IMRT technique. All of the patients were prescribed a total dose of 50 Gy to the whole breast in 2-Gy fractions, followed by a tumor bed boost of 10 Gy in 5 fractions using an electron beam. Results Of all of the patients, 132 (21.2%) received whole breast plus regional lymph node (RLN) irradiation. 438 of 622 patients had records of acute skin toxicity based on common terminology criteria (CTC) for adverse events. Two hundred eighty (64%) patients had Grade 0/1 toxicity, 153 (35%) had Grade 2 and only 4 patients experienced grade 3 toxicity. Seventy patients (16%) had moist desquamation. Univariate analysis revealed that breast planning target volume was the only predictive factor for Grade ≥2 acute dermatitis (P = 0.002). After 4 years, 170 patients reported cosmetic results by self-assessment, of whom 151 (89%) patients reported good/excellent cosmetic results, and 17 (11%) patients reported fair assessments. For invasive cancer, the four-year rate of freedom from locoregional recurrence survival was 98.3%. Regarding carcinoma in situ, no patients experienced recurrence. Conclusion BC patients who underwent conservative surgery followed by inverse IMRT plan exhibited acceptable acute toxicities and clinical outcomes. Longer follow-up is needed.

Postmastectomy radiotherapy reduces locoregional and disease recurrence in patients with stage II–III triple-negative breast cancer treated with neoadjuvant chemotherapy and mastectomy

Background This study investigated the effect of postmastectomy radiotherapy (PMRT) in patients with stage II–III triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC) and modified radical mastectomy (MRM). Patients and methods A total of 104 women with stage II–III TNBC who received NAC and MRM at our institution between January 2000 and July 2007 were identified. Patients were divided into 2 groups (PMRT and non-PMRT) for statistical analysis. Results The median follow-up time was 64 months (range 12–123 months). The 5 year cumulative locoregional recurrence (LRR) and disease recurrence (DR) rates were 26.5% and 49.6%, respectively. Despite their more adverse prognostic features, patients with PMRT had lower 5 year cumulative LRR and DR rates than those without PMRT (LRR: 18.3% vs 52.2%, respectively, p=0.0005; DR: 45% vs 69.1%, p=0.0334, respectively). On multivariate analysis of the entire study cohort, forgoing PMRT was significantly associated with developing LRR and DR. Subset analysis revealed that PMRT significantly reduced the 5 year LRR rate in patients with pre-chemotherapy clinical stages IIA (8.3% vs 46.2%, p=0.019) and IIIA (16% vs 66.7%, p=0.003). PMRT also significantly reduced the 5 year DR rate in patients with pre-chemotherapy clinical stage IIA (24.5% vs 69.3%, p=0.0151) and ≥IIIB (70.8% vs 100%, p=0.0481). Conclusion In our cohort of patients with TNBC treated with NAC and MRM, PMRT significantly improved locoregional control and disease-free survival in the entire cohort as well as in patients with stage IIA disease. Our results may help in tailoring adjuvant treatment decisions for these particular patient populations.

Outcomes Following Salvage Radiation and Systemic Therapy for Isolated Locoregional Recurrence of Breast Cancer after Mastectomy: Impact of Constructed Biologic Subtype

Purpose This study examines factors associated with outcomes following salvage radiation and systemic therapy for breast cancer patients who developed isolated locoregional recurrence (ILRR) after mastectomy alone, while focusing on the prognostic significance of constructed biologic subtype in this setting. Methods and Materials 269 postmastectomy patients in total treated for ILRR were included. Cumulative incidence of locoregional control (LRC), distant metastasis (DM)-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were calculated using Kaplan-Meier method. For statistical analysis, biologic subtypes were constructed from hormonal receptors (Rec) and HER2, consisting of Rec+/HER2-, Rec+/HER2+, Rec-/HER2+, and Rec-/HER2-. The association of clinic-pathological and treatment-related parameters with outcomes was evaluated using a Cox regression model. Results At a median follow-up of 65 months, 56 (20.8%) patients failed to secure LRC after radiotherapy, and 165 patients (61.3%) developed DM. Overall, the actuarial 5-year LRC, DMFS, DFS, and OS rate was 77.3%, 45.6%, 43.9%, and 66.8%, respectively. Multivariate analysis revealed that constructed biologic subtype represented the most significant prognostic factor for any outcome. Compared to patients with Rec+/HER2- disease, those with Rec-/HER2- had significantly poorer 5-year LRC (84.2% versus 58.3%, HR = 4.36, P < 0.001) and worse survivals including 5-year DMFS (63.0% versus 15.8%, HR = 4.28, P < 0.001), DFS (59.7% versus 13.6%, HR=3.92, P < 0.001), and OS (87.8% versus 22.3%, HR = 8.55, P < 0.001). Other factors associated with reduced LRC were no radical surgery and involved field irradiation alone, whereas factors associated with poor survivals included positive nodes at primary diagnosis and regional recurrence. Conclusions Constructed biologic subtypes remained to be predictive of both disease control and survivals after salvage radiation for postmastectomy ILRR. Notably, Rec-/HER2- patients were demonstrated to be at high risk of locoregional failure and subsequent DM and tended to have worse survivals despite salvage therapies.