Cardiac Dysfunction Among Breast Cancer Survivors: Role of Cardiotoxic Therapy and Cardiovascular Risk Factors.

PURPOSE: Cardiac dysfunction is the leading cause of mortality among 10-year breast cancer survivors. Limited information regarding long-term risks of cardiac dysfunction after cardiotoxic therapy (anthracyclines, trastuzumab/pertuzumab, radiation) has precluded development of surveillance guidelines for the survivors. METHODS: Patients with breast cancer who completed cardiotoxic therapy underwent echocardiographic screening every 2 years. New-onset cardiac dysfunction was defined as left ventricular ejection fraction (LVEF) <50% after cardiotoxic therapy initiation and included early- and late-onset cardiac dysfunction. RESULTS: We evaluated 2,808 echocardiograms in 829 breast cancer survivors; the median age at breast cancer diagnosis was 54.2 years (range, 20.3-86.3); the median follow-up was 8.6 years (1.8-39.8); 39.7% received anthracyclines, 16% received trastuzumab/pertuzumab, 6.2% received both anthracyclines and trastuzumab/pertuzumab, and 38.1% received radiation alone. The cumulative incidence of cardiac dysfunction increased from 1.8% at 2 years to 15.3% at 15 years from cardiotoxic therapy initiation. Multivariable Cox regression analysis identified the following risk factors: non-Hispanic Black race (hazard ratio [HR], 2.15 [95% CI], 1.37 to 3.38), cardiotoxic therapies (anthracyclines: HR, 2.35 [95% CI, 1.25 to 4.4]; anthracyclines and trastuzumab/pertuzumab: HR, 3.92 [95% CI, 1.74 to 8.85]; reference: left breast radiation alone), selective estrogen receptor modulators (HR, 2.0 [95% CI, 1.2 to 3.33]), and precancer hypertension (HR, 3.16 [95% CI, 1.63 to 6.1]). Late-onset cardiac dysfunction was most prevalent among anthracycline- and radiation-exposed patients; early-onset cardiac dysfunction was most prevalent among patients exposed to anthracyclines and trastuzumab/pertuzumab; equal prevalence of both early- and late-onset cardiac dysfunction was observed in trastuzumab-/pertuzumab-exposed patients. Adjusted longitudinal analyses revealed an annual decline in LVEF by 0.29% (P = .009) over 20 years from breast cancer diagnosis. CONCLUSION: These findings provide evidence to support echocardiographic surveillance for several years after cardiotoxic therapy and also suggest a need to examine the efficacy of management of cardiovascular risk factors to mitigate risk.

Telephone-Based Rehabilitation Intervention to Optimize Activity Participation After Breast Cancer: A Randomized Clinical Trial.

Importance: Following treatment, breast cancer survivors face challenges participating in valued activities. Objective: To determine whether a telephone-based coaching rehabilitation intervention enhances activity participation in the year following breast cancer treatment. Design, Setting, and Participants: In this multisite, single-blind randomized clinical trial (Optimizing Functional Recovery of Breast Cancer Survivors), recruitment occurred between August 28, 2019, and April 30, 2022. Data collection was completed by April 1, 2023. Participants were recruited from 2 cancer centers (Dartmouth College and the University of Alabama at Birmingham) and via social media advertisements. Women aged 18 years or older who had completed primary treatment for stage I to III breast cancer within 1 year and reported participation restrictions were eligible to participate. Randomization was stratified by site, treatment, and time since treatment. Interventions: The intervention, delivered via telephone over 9 sessions, used behavioral activation and problem-solving principles to promote activity participation. The education-based attention control condition was delivered via telephone at matched intervals. Main Outcomes and Measures: The primary outcome was participation, assessed using 5 measures, including Patient-Reported Outcomes Measurement Information System (PROMIS) social participation-satisfaction measure. One individualized outcome allowed participants to specify activities for which they wanted to foster recovery. Outcomes were collected by telephone by blinded coordinators at baseline and at 8, 20, and 44 weeks. The individualized outcome was assessed at the first and last intervention and control session. Results: Among 1996 patients identified, 303 were eligible and enrolled. Of these, 284 women (94%; mean [SD] age, 56.1 [10.2] years) completed baseline assessments and were randomized, and 81% or more of each group completed the final assessment with no adverse events. Of those who completed the final assessment, 118 of 114 (82%) were in the intervention group, and 113 of 140 (81%) were attention control participants. Between-group differences were not statistically significant for the main measures of PROMIS satisfaction (week 20: Cohen d, 0.1 [95% CI, -0.09 to 0.29] and week 44: Cohen d, -0.08 [95% CI, -0.27 to 0.11]) and ability (week 20: Cohen d, 0.15 [95% CI, -0.06 to 0.37] and week 44: Cohen d, -0.08 [95% CI, -0.27 to 0.11]). On the individualized outcome, intervention participants reported significantly greater improvements in activity satisfaction (Cohen d, 0.76 [95% CI, 0.48-1.02]) and performance (Cohen d, 0.60 [95% CI, 0.32-0.87]). Conclusions and Relevance: In this randomized clinical trial, the intervention catalyzed greater improvements in self-selected activity participation and goal disengagement but did not otherwise accelerate recovery compared with the control condition. Future research should determine what intervention features may lead to the greatest reductions in participation restrictions and other measures that may detect functional recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT03915548.

Acute Toxicity of Total Body Irradiation Using Volumetric Arc Therapy With a Focus on the Effect of Lung Dose Rate.

Purpose: To report adverse effects of high dose total body irradiation (TBI) delivered using a volumetric arc therapy (VMAT) technique and to assess pulmonary toxicity at dose rates of 40 and 100 monitor units per minute (MU/min). Methods and Materials: This retrospective study included patients >18 years old who received ≥8 Gy TBI using a VMAT technique. The TBI dose was prescribed to a planning target volume consisting of a 0.5 cm retraction of the body with the lungs subtracted. The objective function specified planning target volume coverage goals of D100% ≥ 90% and Dmax <130%. A lung dose control structure consisting of a 1 cm retraction of the lung volume was limited to Dmean <75%. Treatments were initially delivered with a dose rate of 40 MU/min for the thoracic isocenters and 100 MU/min for the other isocenters. Beginning in January 2021, a dose rate of 100 MU/min was used for all isocenters. All treatments were administered in 2 Gy fractions delivered twice daily. Acute toxicity was assessed for 30 days after TBI. Results: A total of 29 patients were included in this analysis who received TBI between January 2019 and October 2021. Prescription dose ranged from 8 to 12 Gy. Mean lung dose was 7.9 Gy (SD, 1.4 Gy) for patients treated at 40 MU/min and for patients treated at 100 MU/min 7.1 Gy (SD, 1.3 Gy). Mucositis was the most common grade 3 toxicity and occurred in 10 (34%) patients. Only 1 instance of pneumonitis was observed and occurred in a patient who received a mean lung dose of 10.1 Gy delivered at 40 MU/min. Conclusions: In this cohort of patients who received high dose TBI using a VMAT technique, the composite rate of acute toxicity was not unexpectedly high. We did not observe an increase in lung toxicity after increasing the dose rate of the thoracic isocenters from 40 MU/min to 100 MU/min.

Effects of Radiation Therapy on the Female Reproductive Tract in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

PURPOSE: The PENTEC (Pediatric Normal Tissue Effects in the Clinic) task force aimed to quantify effects of radiation therapy (RT) dose to the female reproductive organs after treatment for childhood cancer. METHODS AND MATERIALS: Relevant studies published 1970 to 2017 were identified systematically through PubMed, Medline, and Cochrane databases with additional articles before 2021 identified by the group. Two large studies reported sufficient data to allow modeling of acute ovarian failure (AOF; loss of function ≤5 year from diagnosis) and premature ovarian insufficiency (POI; loss of function at attained age <40 years) based on maximum dose to least affected ovary. Although normal tissue complication probability modeling was not feasible for the uterus due to limited data, the relationship between ultrasound-measured uterine volume and estimated amount of RT was plotted. Limited data regarding vaginal toxicity were available. RESULTS: The risk of AOF increases with RT dose to least affected ovary, alkylating agent cumulative dose (cyclophosphamide equivalent dose [CED] in g/m2), age at RT, and stem cell transplantation: Two Gy to the least affected ovary resulted in AOF risk of 1% to 5% (CED = 0, risk increasing with age), 4% to 7% (CED = 10 g/m2, risk increasing with age), and 6% to 13% (CED = 30 g/m2, risk increasing with age). For patients aged 1 and 20 years at time of RT, AOF risk was ≥50% at doses of 24 Gy and 20 Gy with no alkylating chemotherapy, 22.5 Gy and 17 Gy with intermediate alkylator dose (10 g/m2), and 17 Gy and 13 Gy with high alkylator dose (30 g/m2). Risk of POI increases with survivor (attained) age (rather than age at time of RT), radiation dose to least affected ovary, and alkylator dose. Data review suggested that higher radiation doses to the uterus are associated with uterine toxicity, with uterine size considerably restricted after 12 Gy. Vaginal radiation in children is associated with high toxicity risk, although dose-volume data are not available for quantification. CONCLUSIONS: Risk of AOF increases with age at RT, CED exposure, and RT dose; risk of POI likewise increases with RT dose, CED exposure, and survivor age. Both AOF and POI are expected to affect fertility and estrogen production. Data suggest that RT uterine dose >12 Gy may be associated with uterine size restriction. Adult literature suggests that maintaining vaginal dose <5 Gy may limit toxicity. Treatment of life-threatening malignancy remains a priority over reproductive preservation; however, when possible, radiation and surgical techniques should be considered to minimize dose to least affected ovary, uterus, and vagina. Survivors should receive endocrine and gynecologic support; those desiring pregnancy should be counseled early to maximize reproductive options.

Enhancing Efficiency and Reach Using Facebook to Recruit Breast Cancer Survivors for a Telephone-Based Supportive Care Randomized Trial During the COVID-19 Pandemic.

PURPOSE: Evidence supporting social media-based recruitment of cancer survivors is limited. This paper describes how we used Facebook during the COVID-19 pandemic to augment our recruitment of breast cancer survivors for our two-site telephone-based randomized clinical trial (RCT) at Dartmouth-Hitchcock Medical Center and the University of Alabama at Birmingham. METHODS: Originally a two-site RCT of a telephone-delivered breast cancer survivorship intervention, we extended our clinic-based recruitment to Facebook. Participant characteristics, geographic reach, and baseline outcomes were compared across recruitment sources (ie, two clinics and Facebook) using descriptive statistics and effect sizes. RESULTS: Enrollment rates (20%-29%) were comparable across recruitment sources. The 21-month Facebook marketing campaign accounted for 59% (n = 179/303) of our total sample and had the greatest geographic reach, recruiting women from 24 states. The Facebook campaign reached a total of 51,787 unique individuals and cost $88.44 in US dollars (USD) per enrolled participant. Clinic samples had a greater proportion of women who were widowed (8% v 1%; P = .03) and Facebook had a higher proportion of women with a household income over $40,000 USD (83% v 71%; P = .02). There were no statistically significant differences between Facebook and the two clinics on baseline survey scores. CONCLUSION: Augmenting traditional recruitment with Facebook increased our RCT's geographic and sociodemographic reach and supported meeting recruitment goals in a timely way. In the wake of the COVID-19 pandemic, cancer survivorship researchers should consider using social media as a recruitment strategy while weighing the advantages and potential biases introduced through such strategies.

Feasibility and Short-Term Toxicity of a Consecutively Delivered Five Fraction Stereotactic Body Radiation Therapy Regimen in Early-Stage Breast Cancer Patients Receiving Partial Breast Irradiation.

Background: For appropriately selected patients with early-stage breast cancer (ESBC), accelerated partial breast irradiation (APBI) yields equivalent rates of ipsilateral breast tumor recurrence with mixed results in patient-rated cosmesis compared with whole-breast radiotherapy depending on the technique utilized. When utilizing external beam radiotherapy for APBI, techniques to reduce target margins and overall treatment volume are potentially important to decrease rates of long-term adverse cosmesis. Stereotactic body radiotherapy (SBRT) is a promising technique to deliver APBI because of its increased accuracy and sparing of uninvolved breast tissue. We report the initial results of a prospective clinical trial investigating feasibility, safety, and cosmetic outcomes of a daily five-fraction SBRT regimen for APBI. Methods: Twenty-three patients with ESBC after lumpectomy who met APBI suitability were enrolled. During lumpectomy, a bioabsorbable three-dimensional fixed array tissue marker (BioZorb™, Hologic, Marlborough, MA) was placed for enhanced visualization of the cavity boundaries. Clinical target volume (CTV) was defined as the delineable cavity plus a 1-cm isotropic expansion followed by a 3-mm isotropic planning target volume (PTV) expansion. Patients received 30 Gy delivered in five planned consecutive daily fractions in either prone or supine positioning depending on individual anatomy. Two patients completed the five-fraction treatments in 9-day interval and 11-day interval due to external circumstances. A maximum PTV of 124cc was allowed to minimize incidence of fat necrosis. Plans utilized 10-MV flattening filter-free beams delivered on a Varian Edge linear accelerator. Local control, toxicity, and nurse/patient-scored cosmesis at pre-treatment baseline, 1 month post-treatment, and at subsequent 6-month intervals were recorded. Results: Twenty-three patients were accrued at the time of submission with median follow-up of 6 months. No patients experienced grade ≥3 acute toxicity. Of the 10 events reported probably related to SBRT, nine were grade 1 (n = 9/10, 90%). There was no evidence of difference, deterioration, or change in patient or nurse-scored cosmesis from baseline to 1 and 6 months post-treatment. One patient developed nodal failure shortly after APBI. Conclusions: Although longer follow-up is needed to assess long-term toxicity and local control, this study demonstrated a five-fraction SBRT regimen delivered over consecutive days is a safe, efficient, well-tolerated, and cosmetically favorable means of delivering APBI in suitable women. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03643861, NCT03643861.

Bloom where you are planted: Hemangioma or malignancy?

Vascular anomalies comprise a spectrum of disorders characterized by the abnormal development or growth of blood and lymphatic vessels. These growths have unique features and diverse behaviors, mandating a multidisciplinary approach in their evaluation, diagnosis, and management. Here we describe the case of a male toddler presenting with an abdominal mass, originally treated as a metastatic retroperitoneal tumor, but subsequently felt to represent a vascular anomaly.

Dosimetric Evaluation Between the Conventional Volumetrically Modulated Arc Therapy (VMAT) Total Body Irradiation (TBI) and the Novel Simultaneous Integrated Total Marrow Approach (SIMBa) VMAT TBI.

Purpose The purpose of this study was to assess the treatment planning feasibility of volumetrically modulated arc therapy total body irradiation (VMAT TBI) using a simultaneous integrated marrow and body approach (SIMBa). We also aimed to compare SIMBa TBI with the more conventional VMAT TBI approach using the entire body as the target. The goal of using an integrated approach like SIMBa is to balance the known clinical benefit of TBI with the toxicity decrease of Total Marrow Irradiation (TMI) using two prescription volumes. In anticipation of a clinical trial to investigate a novel conditioning regimen that uses SIMBa, our institution retrospectively analyzed the dosimetric differences between 20 clinical VMAT TBI which were re-planned using SIMBa. Methods Twenty patients who previously received conventional VMAT TBI at our institution with a dose of 12 Gy in six fractions were re-planned using SIMBa with a planning aim of delivering a uniform dose of 12 Gy to at least 90% of the PTV_BodyEval. The planning aims of SIMBa were to deliver a uniform dose of 12 Gy to at least 90% of the PTV_Marrow and 8 Gy to at least 90% of the PTV_TotalBody while limiting the mean lung dose to less than 8 Gy. The plans were normalized so that 100% of the PTV_Marrow received at least 90% of the dose with the PTV_TotalBody optimized to stay as close to 100% at 90% as possible. Results All 20 patient plans achieved 12 Gy/8 Gy to at least 90% of the PTV_Marrow and PTV_TotalBody, respectively, with max doses of <16 Gy (130%). As compared with the delivered TBI, the following reductions in mean dose were notable: small bowel 21.3±4.2%, lung 16.3±7.9%, heart 25.3±8.6%, and kidney 16.4±6.2%. Coverage of the sanctuary sites was maintained despite a significant reduction to sensitive organs at risk (OARs). Conclusion This study supports that VMAT TBI treatment planning with SIMBa is feasible. In this sample, SIMBa provided dosimetrically similar doses to marrow and sanctuary site doses as TBI while achieving lower doses to OARs. A clinical trial is needed to investigate the clinical implications of VMAT TBI with SIMBa.

Study protocol for a multisite randomised controlled trial of a rehabilitation intervention to reduce participation restrictions among female breast cancer survivors.

INTRODUCTION: Many breast cancer survivors report an inability to fully participate in activities of daily living after completing cancer treatment. Reduced activity participation is linked to negative consequences for individuals (eg, depression, reduced quality of life) and society (reduced workforce participation). There is currently a lack of evidence-based interventions that directly foster cancer survivors' optimal participation in life roles and activities. Pilot study data suggest rehabilitation interventions based on behavioural activation (BA) and problem-solving treatment (PST) can facilitate post-treatment role resumption among breast cancer survivors. METHODS AND ANALYSIS: This protocol describes a multisite randomised controlled trial comparing a 4-month long, nine-session BA and PST-informed rehabilitation intervention (BA/PS) against a time-matched, attention control condition. The overall objective is to assess the efficacy of BA/PS for enhancing breast cancer survivors' activity participation and quality of life over time. A total of 300 breast cancer survivors reporting participation restrictions after completing curative treatment for stage 1-3 breast cancer within the past year will be recruited across two sites (Dartmouth-Hitchcock Medical Center and University of Alabama at Birmingham). Assessments are collected on enrolment (T1) and 8 (T2), 20 (T3) and 44 (T4) weeks later. ETHICS AND DISSEMINATION: Study procedures are approved by the Committee for the Protection of Human Subjects at Dartmouth College, acting as the single Institutional Review Board of record for both study sites (STUDY 00031380). Results of the study will be presented at national meetings and submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03915548; Pre-results.

Hypofractionated radiation in older women with breast cancer.

BACKGROUND: American Society of Radiation Oncology Choosing Wisely campaign recommends hypofractionated radiation and against routine use of intensity-modulated radiation therapy (IMRT) in early-stage estrogen receptor-positive breast cancer. We analyzed guideline recommendation adherence and financial implications in a modern Medicare cohort of women treated across the southeastern United States. METHODS: Our study population comprised Medicare patients over 65 years of age with breast cancer diagnosis from 12 cancer centers in the Southeast United States with stage 0-II breast treated with lumpectomy from 2012 to 2015. Hypofractionation was defined as 4 or fewer weeks of radiation treatments. Factors associated with utilization of hypofractionation and IMRT were identified using Poisson regression. Median costs during radiation treatments were compared for hypofractionation and IMRT. RESULTS: In older women (median age 71), 75% were treated with conventional fractionation, and 20% received IMRT. Hypofractionated women were more likely to have a positive estrogen(ER) or progestorone(PR) receptor status, lower comorbidity scores, and be treated at a high volume center (all P < 0.05). IMRT was utilized in 20% of patients and was more common in women treated with conventional fractionation (P < 0.001). Positive ER/PR status (P < 0.001) and utilization of hormonal blockade (P = 0.02) were associated with increased utilization of IMRT. CONCLUSION: In an older cohort of patients with early-stage breast cancer, a majority were treated with conventional fractionated radiation, while approximately 20% were treated with IMRT. Both of which were associated with increased cost relative to hypofractionation.

Molecular determinants of post-mastectomy breast cancer recurrence.

Breast cancer (BC) adjuvant therapy after mastectomy in the setting of 1-3 positive lymph nodes has been controversial. This retrospective Translational Breast Cancer Research Consortium study evaluated molecular aberrations in primary cancers associated with locoregional recurrence (LRR) or distant metastasis (DM) compared to non-recurrent controls. We identified 115 HER2 negative, therapy naïve, T 1-3 and N 0-1 BC patients treated with mastectomy but no post-mastectomy radiotherapy. This included 32 LRR, 34 DM, and 49 controls. RNAseq was performed on primary tumors in 110 patients; with no difference in RNA profiles between patients with LRR, DM, or controls. DNA analysis on 57 primary tumors (17 LRR, 15 DM, and 25 controls) identified significantly more NF1 mutations and mitogen-activated protein kinase (MAPK) pathway gene mutations in patients with LRR (24%, 47%) and DM (27%, 40%) compared to controls (0%, 0%; p < 0.0001 and p = 0.0070, respectively). Three patients had matched primary vs. LRR samples, one patient had a gain of a NF1 mutation in the LRR. There was no significant difference between the groups for PTEN loss or cleaved caspase 3 expression. The mean percentage Ki 67 labeling index was higher in patients with LRR (29.2%) and DM (26%) vs. controls (14%, p = 0.0045). In summary, mutations in the MAPK pathway, specifically NF1, were associated with both LRR and DM, suggesting that alterations in MAPK signaling are associated with a more aggressive tumor phenotype. Validation of these associations in tissues from randomized trials may support targeted therapy to reduce breast cancer recurrence.

Lower frequency of TLR9 variant associated with protection from breast cancer among African Americans.

INTRODUCTION: Toll-like receptor 9 (TLR9) is an innate immune system DNA-receptor that regulates tumor invasion and immunity in vitro. Low tumor TLR9 expression has been associated with poor survival in Caucasian patients with triple negative breast cancer (TNBC). African American (AA) patients with TNBC have worse prognosis than Caucasians but whether this is due to differences in tumor biology remains controversial. We studied the prognostic significance of tumor Toll like receptor-9 (TLR9) protein expression among African American (AA) triple negative breast cancer (TNBC) patients. Germline TLR9 variants in European Americans (EAs) and AAs were investigated, to determine their contribution to AA breast cancer risk. METHODS: TLR9 expression was studied with immunohistochemistry in archival tumors. Exome Variant Server and The Cancer Genome Atlas were used to determine the genetic variation in the general EA and AA populations, and AA breast cancer cases. Minor allele frequencies (MAFs) were compared between EAs (n = 4300), AAs (n = 2203), and/or AA breast cancer cases (n = 131). RESULTS: Thirty-two TLR9 variants had a statistically significant MAF difference between general EAs and AAs. Twenty-one of them affect a CpG site. Rs352140, a variant previously associated with protection from breast cancer, is more common in EAs than AAs (p = 2.20E-16). EAs had more synonymous alleles, while AAs had more rare coding alleles. Similar analyses comparing AA breast cancer cases with AA controls did not reveal any variant class differences; however, three previously unreported TLR9 variants were associated with late onset breast cancer. Although not statistically significant, rs352140 was observed less frequently in AA cases compared to controls. Tumor TLR9 protein expression was not associated with prognosis. CONCLUSIONS: Tumor TLR9 expression is not associated with prognosis in AA TNBC. Significant differences were detected in TLR9 variant MAFs between EAs and AAs. They may affect TLR9 expression and function. Rs352140, which may protect from breast cancer, is 1.6 X more common among EAs. These findings call for a detailed analysis of the contribution of TLR9 to breast cancer pathophysiology and health disparities.

PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers.

Previous studies have shown that basal breast cancers, which may have an inherent "BRCAness" phenotype and sensitivity to inhibitors of poly (ADP-Ribose) polymerase (PARP), express elevated levels of PARP1. Our lab recently reported that HER2+ breast cancers also exhibit sensitivity to PARP inhibitors (PARPi) by attenuating the NF-κB pathway. In this study, we assessed PARP1 and phospho-p65, a marker of activated NF-κB levels in human breast cancer tissues. PARP1 and PARP2 copy number, mRNA, and protein expression was assessed by interrogating the PAM-50 defined breast cancer patient set from the TCGA using cBioPortal. PARP1 and phospho-p65 immunohistochemistry and correlation to clinical parameters was conducted using 307 primary breast cancer specimens (132 basal, 82 luminal, 93 HER2+) through univariate and multivariate analyses. In the PAM50 breast cancer data set, PARP1 and 2 expression was altered in 24/58 (41 %) HER2+, 32/81 (40 %) basal, and 75/324 (23 %) luminal A/B breast cancer patients. This correlated with a statistically significant increase in PARP1 protein levels in HER2+ and basal but not luminal breast cancers (p = 0.003, p = 0.027, p = 0.289, respectively). No change in PARP2 protein level was observed. Interestingly, using breast cancer specimens from 307 patients, HER2 positivity correlated with elevated PARP1 expression (p < 0.0001) and was three times more likely than HER2 negative breast cancers to exhibit high PARP1 levels. No significant differences were noted between race, ER status, or PR status for PARP1 expression. Additionally, we found a significant correlation between HER2 status and phospho-p65 expression (p < 0.0001). Lastly, a direct correlation between PARP1 and phospho-p65 (p < 0.0001) was noted. These results indicate a potential connection between HER2, PARP1, and phospho-p65. Furthermore, these data suggest that the PARPi sensitivity we previously observed in HER2+ breast cancer cells may be due to elevated PARP1 expression.

Patterns of Failure for Lymph Node-Positive Resected Pancreatic Adenocarcinoma After Adjuvant Radiotherapy or Gemcitabine-based Chemotherapy Alone.

PURPOSE: The purpose of this study was to investigate the effect of radiotherapy on local control and mordibity for patients with resected lymph node-positive pancreatic cancer as compared to gemcitabine-based chemotherapy alone. MATERIALS AND METHODS: Sixty-nine patients received adjuvant therapy for pancreatic adenocarcinoma with lymph node involvement after surgical resection and met the inclusion criteria for this analysis. Forty (58 %) patients received postoperative radiotherapy (PORT) to a median dose of 50.4 Gy with capecitabine or 5-fluorouracil concurrently in all but one case; 15 patients also received gemcitabine prior to PORT. Twenty-nine (42 %) patients received gemcitabine-based chemotherapy without PORT for a median of 6 cycles. RESULTS: The median overall survival for patients receiving PORT was 24.4 months compared to 25.6 months for patients not receiving PORT (p = 0.943). At 2 years, the rate of local control was 57 % for patients receiving PORT compared to 37 % for those who did not (p = 0.034). At 2 years, the rate of palliative local interventions was 16 % for patients receiving PORT compared to 18 % for patients who did not (p = 0.821). CONCLUSION: The use of PORT was associated with improved local control in the gemcitabine era for patients with resected, node-positive, pancreatic adenocarcinoma. The rates of overall survival and palliative interventions did not differ between the two groups.

Adjuvant stereotactic body radiotherapy following transarterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of ≥ 3 cm.

OBJECTIVES: The optimal locoregional treatment for non-resectable hepatocellular carcinoma (HCC) of ≥ 3 cm in diameter is unclear. Transarterial chemoembolization (TACE) is the initial intervention most commonly performed, but it rarely eradicates HCC. The purpose of this study was to measure survival in HCC patients treated with adjuvant stereotactic body radiotherapy (SBRT) following TACE. METHODS: A retrospective study of patients with HCC of ≥ 3 cm was conducted. Outcomes in patients treated with TACE alone (n = 124) were compared with outcomes in those treated with TACE + SBRT (n = 37). RESULTS: There were no significant baseline differences between the two groups. The pre-TACE mean number of tumours (P = 0.57), largest tumour size (P = 0.09) and total tumour diameter (P = 0.21) did not differ significantly between the groups. Necrosis of the HCC tumour, measured after the first TACE, did not differ between the groups (P = 0.69). Local recurrence was significantly decreased in the TACE + SBRT group (10.8%) in comparison with the TACE-only group (25.8%) (P = 0.04). After censoring for liver transplantation, overall survival was found to be significantly increased in the TACE + SBRT group compared with the TACE-only group (33 months and 20 months, respectively; P = 0.02). CONCLUSIONS: This retrospective study suggests that in patients with HCC tumours of ≥ 3 cm, treatment with TACE + SBRT provides a survival advantage over treatment with only TACE. Confirmation of this observation requires that the concept be tested in a prospective, randomized clinical trial.

Quantitative perfusion- and diffusion-weighted magnetic resonance imaging of gastrointestinal cancers treated with multikinase inhibitors: a pilot study.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) are often used to detect the early response of solid tumors to an effective therapy. The early changes in intratumoral physiological parameters measured by DCE-MRI/DWI have been evaluated as surrogate biomarkers allowing a tailored treatment for the individual patient. METHODS: Patients with newly diagnosed, biopsy-proven, treatment-naïve gastrointestinal stromal tumor (GIST) or hepatocellular carcinoma (HCC) were enrolled prospectively after institutional review board (IRB)-approved informed consent (5 patients per tumor type). Patients with GIST were treated with sunitinib over 6 weeks. DCE-MRI/DWI was applied before therapy (baseline imaging) and at 2 and 6 weeks after therapy initiation. Patients with HCC were treated with radiation during the first 2 weeks and then with sorafenib for the next 6 weeks. DCE-MRI/DWI was applied in all patients with HCC before and after radiation therapy and at the end of sorafenib therapy. Tumor volume, perfusion parameters (K (trans), the forward volume-transfer constant, and k ep, the reverse reflux-rate constant) and the apparent diffusion coefficient (ADC) were measured. RESULTS: During 2 weeks of sunitinib therapy, GIST volume, K (trans), and k ep decreased 32 ± 13, 45 ± 24, and 42 ± 15%, respectively, whereas ADC increased 76 ± 24%. After 6 weeks of sunitinib therapy, GIST volume, K (trans), and k ep decreased 56 ± 7, 70 ± 7, and 50 ± 12%, respectively, whereas ADC increased 85 ± 33%. After completion of radiation therapy, HCC volume, K (trans), and k ep decreased 34 ± 14, 35 ± 12, and 4 ± 21%, respectively, but ADC increased 21 ± 9%. During the entire 10-week therapeutic period, HCC volume, K (trans), and k ep decreased 65 ± 15, 40 ± 9, and 26 ± 2%, respectively, whereas ADC increased 28 ± 10%. CONCLUSION: DCE-MRI/DWI can measure the perfusion and diffusion changes in GISTs or HCCs treated with multikinase inhibitors.

Accelerated partial breast irradiation for early-stage breast cancer: controversies and current indications for use.

Radiation therapy options for early-stage breast cancer have evolved during the past 40 years. Several choices are currently available to certain patient subsets that allow radiation oncologists to individualize care. Multiple phase II and several phase III trials have been published that support the safety and efficacy of accelerated partial breast irradiation (APBI) as part of breast conservation in selected patients. In contrast, a recent large retrospective analysis of patients aged 67 or older who received brachytherapy for APBI has raised concerns about its effectiveness. As the radiation community awaits results from NSABP B-39/RTOG 0413, the largest randomized trial of whole breast radiation therapy (WBRT) versus APBI, to provide more conclusive data, many academic and private radiation oncology practices are utilizing APBI off-protocol to treat early-stage breast cancer patients. Because of this, the American Society for Radiation Oncology (ASTRO) published a consensus statement in 2009 to aid in proper patient selection (Table 1). Until more definitive data is garnered, we advocate strict adherence to these selection criteria to ensure optimal outcomes. Specifically, we caution against the use of APBI in lymph node-positive disease outside of a clinical trial. There is a paucity of comparative data to guide oncologists in selection of the best APBI delivery method. The current NSABP B-39/RTOG 0413 trial allows any of the three most common forms of delivery to be utilized (multicatheter interstitial brachytherapy, balloon intracavitary brachytherapy, and external beam 3D conformal therapy) and will be instrumental to compare outcome differences between these methods.

Accuracy of breast magnetic resonance imaging in predicting pathologic response in patients treated with neoadjuvant chemotherapy.

BACKGROUND: Prior studies of the ability of magnetic resonance imaging (MRI) to predict pathologic response to neoadjuvant chemotherapy have shown conflicting results that vary depending on baseline molecular characteristics. This study examines the ability of MRI to predict pathologic complete response (pCR) and explores the influence of tumor molecular profiles on MRI sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). METHODS: Eighty-one patients with invasive breast cancer treated with neoadjuvantsystemic therapy between 2002 and 2009 who were imaged with breast MRI pre- and post-treatment were reviewed. Patient, tumor, and treatment characteristics were recorded. Comparisons of molecular subsets and their influence on MRI sensitivity, specificity, PPV, and NPV were made using χ(2)contingency tables. RESULTS: The sensitivity, specificity, PPV, and NPV of MRI for predicting pCR for the total group were 92%, 50%, 74%, and 80%, respectively. Patients had the following molecular subtypes: 33/81 (41%) HR+Her2-, 23/81 (28%) HR+/-Her2 +, and 25/81(31%) triple receptor negative (TN). Molecular subtype did not demonstrate a significant correlation of radiographic and pathologic response, although MRI NPV was highest in the TN subset (100%) followed by those with HR+/-Her2+ disease (87.5%). Multivariate analysis did not show that tumor characteristics (estrogen receptor status, progesterone receptor status, HER2 status) or neoadjuvant treatment (doxorubicin, cyclophosphamide, paclitaxel versus other or trastuzumab) had any effect on MRI sensitivity or specificity. CONCLUSIONS: In patients receiving neoadjuvant systemic therapy for invasive breast cancer, molecular subtype and systemic regimen administered did not significantly influence the sensitivity, specificity, PPV, or NPV of MRI in predicting pathologic response.

Dosimetric analysis of imaging changes following pulmonary stereotactic body radiation therapy.

INTRODUCTION: The aim of this study was to determine whether late patterns of pulmonary fibrosis are related to specific radiation doses administered during thoracic stereotactic body radiation therapy (SBRT). METHODS: The records of all patients treated with SBRT for either pulmonary metastases or inoperable primary lung tumours at the University of Alabama at Birmingham from November 2005 to July 2008 were reviewed. Patients selected for analysis had diagnostic chest computed tomography (CT) scans acquired at least 180 days after completion of therapy. CT scans acquired at follow-up were co-registered with the original treatment planning CT scans for 12 eligible patients (17 lesions), and late-occurring pulmonary imaging abnormalities (IAs) were contoured. Dosimetric parameters analysed include D(80) , D(90) , V(18) and V(prescription dose) of the IA and V(14) and V(18) of the lung. RESULTS: Late pulmonary IAs were identified in 11 treated areas from nine patients. Late IAs could not be identified in six treated areas from three patients secondary to emphysema, tumour progression and severe atelectasis, respectively. The mean doses to 80% (D(80) ) and 90% (D(90) ) of the IAs were 18.4 and 14.5 Gy, respectively (ranges: 5.6-27.8 and 3.3-22.4 Gy). On average, 79.4% (range: 45.6-97.5%) of the IA received at least 18 Gy, while an average of 19.3% (range: 0.2-42.2%) received the prescription dose. On average, only 4.2% (range: 1.1-7.8%) of the lungs received 18 Gy. CONCLUSION: Imaging abnormalities consistent with pulmonary fibrosis are common after SBRT and are well approximated by the 18 Gy isodose distribution. The clinical ramification of these findings should be evaluated in future studies.

Intensity-modulated radiotherapy outcomes for oropharyngeal squamous cell carcinoma patients stratified by p16 status.

BACKGROUND: Patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with intensity-modulated radiotherapy (IMRT) were stratified by p16 status, neck dissection, and chemotherapy to correlate these factors with outcomes. METHODS: A total of 112 patients with OPSCC treated with IMRT from 2002 to 2008 were retrospectively analyzed. All patients received RT to 66-70 Gray. Forty-five of the tumors were p16 positive (p16+), 27 were p16 negative (p16-), and 41 had unknown p16 status. Sixty-two patients had postradiation neck dissections. Nine patients with p16- tumors and 28 patients with p16+ tumors received chemotherapy. The distribution of T, N, and stage grouping among the p16+ and p16- patients was not significantly different, and 87.5% patients had stage III/IV disease. RESULTS: The median follow-up was 26.3 months. For patients with p16+ tumors, p16- tumors, and the overall cohort, the actuarial 3-year locoregional progression-free survival rate was 97.8%,73.5%, and 90.5% respectively (P = .006) and the disease-free survival rate was 88.2%, 61.4%, and 81.7%, respectively (P = .004). Patients with p16+ tumors had an 89.5% and 87.5% pathologic complete response (CR) on neck dissection with and without chemotherapy, respectively. In contrast, patients with p16- tumors had a 66.7% and 25.0% pathologic CR on neck dissection with and without chemotherapy, respectively. CONCLUSIONS: In this series, p16 status was found to be a significant predictive biomarker and patients with p16+ tumors had much better outcomes than patients with p16- tumors. Further investigation is warranted to determine whether less intense therapy is appropriate for selected patients with p16+ OPSCC, whereas more aggressive strategies are needed to improve outcomes in patients with p16- disease.