K.S. Keene

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

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.

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.

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.

An imrt technique to increase therapeutic ratio of breast irradiation in patients with early-stage left breast cancer: limiting second malignancies

The clinical application of intensity modulated radiotherapy (IMRT) for adjuvant treatment of breast cancer has been the subject of increasing study in recent years. IMRT results in improved target coverage, reduced dose inhomogeneity within the breast, and reduced dose to the heart, lungs, and contralateral breast. However, this has been at the cost of larger volumes of low-dose radiation to these structures, thus increasing the theoretic risk for second malignancies. Our goal was to develop an IMRT beam arrangement that did not result in additional low-dose spill to organs at risk while maintaining equal or better target coverage. Five patients with early-stage left-sided breast cancer, who underwent breast conservation surgery and adjuvant radiation therapy, were chosen for this comparative study. The conventional radiation treatment (CRT) plan was comprised of standard wedged tangential fields. An IMRT plan consisting of 6 tangential beams (3 medial and 3 lateral) was generated by using the gantry, collimator, and table angles of the standard plan used for the CRT plan, and moving the table +10 degrees and -10 degrees on each side. The prescription dose for both CRT and IMRT plans was 45 Gy, 1.8 Gy/fraction, prescribed to the isocenter, which was placed near the center of the breast. IMRT plans provided significantly better coverage of the left breast than the CRT plans (p = 0.03). Although the dose heterogeneity was greater with the IMRT plans, the difference was not significant (p = 0.68). The mean volumes of the heart, lung, and right breast were lower in patients planned with IMRT at all dose levels from 5% to 100% dose (5% increments). This difference was significant for volumes receiving 2.25 Gy for the heart (p = 0.003), and volumes receiving 2.25, 4.5, 6.75, 33.75, 36, 38.25, and 42.75 Gy for the lung (p = 0.014, 0.04, 0.044, 0.05, 0.049, 0.045, and 0.05, respectively). Surprisingly, breast IMRT resulted in significantly lower right breast volumes irradiated at all dose levels compared to CRT. A 6-tangential-field IMRT technique achieved significantly better left breast coverage while maintaining lower doses to risk organs at all dose levels and therefore reduced the potential for induction of a second malignancy.

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).

Abstract P3-03-03: A tri-modality imaging assessment algorithm to evaluate neoadjuvant therapy response in patients with operable breast cancer

Background: To determine the negative predictive value (NPV), positive predictive value (PPV), accuracy, sensitivity and specificity of a pre-surgical tri-modality imaging assessment algorithm to determine complete pathologic response (pCR) post neoadjuvant therapy in patients with operable breast cancer. Methods: A retrospective analysis was performed on data collected from patients receiving neoadjuvant therapy and pre-surgical breast magnetic resonance imaging (MRI), ultrasound (US) and mammography between 2004 and 2010 at our institution. Tri-modality imaging was reviewed by a single blinded breast radiologist and evaluated for predetermined modality specific parameters as defined in Table 1. The NPV, PPV, accuracy, sensitivity, and specificity were calculated on the basis of the final surgical pathology report with a complete pathologic response in the breast defined as no residual invasive disease or in situ disease. Results. Eighty-three tumors in 83 patients with a mean age of 50 (range 27–70) were evaluated. Twenty-three patients had a pCR. The NPV, PPV, sensitivity, specificity, and accuracy of tri-modality imaging algorithm for pCR were 0.87, 0.95, 0.95, 0.87 and 0.93 utilizing a cut-point of ≤ 5 for complete response by imaging. The mean score for patients with pCR was 4.61 (range 3–10) with 3 patients scoring above 5. The mean score for patients with residual disease was 7.73 (range 5–11). Conclusions: A tri-modality imaging scoring algorithm is predictive of complete pathologic response. This algorithm will be tested in a developing prospective trial that will also assess the additive value of tumor bed biopsy in patients who achieve a score of 5 or less. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-03-03.

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.Genomics: NF1 mutations more frequent in recurrent breast cancerWomen with breast cancer who relapse following surgery frequently harbor genomic alterations in a pathway linked to cell proliferation and anti-tumor immune responses. A USA-based team led by Funda Meric-Bernstam from the University of Texas MD Anderson Cancer Center in Houston, and Kimberly Keene from the University of Alabama at Birmingham conducted a thorough molecular analysis of tumor samples obtained from 115 women with 5 years of follow-up after a mastectomy and, oftentimes, adjuvant chemotherapy or hormonal therapy. RNA profiles did not significantly differ between women who experienced local recurrence, developed distant metastases or were still in remission. However, DNA analyses identified significantly more mutations in patients whom recurred in the mitogen-activated protein kinase cell signaling pathway, specifically NF1, implicated in cell growth and immunity. If validated, the findings support targeting this pathway to prevent disease recurrence.

Abstract B37: Increased expression of poly (ADP-ribose) polymerase (PARP) and phospho-p65 in human HER2+ breast cancer

Background: Despite the efficacy of targeted agents against the HER2 receptor, many patients with HER2+ breast cancer will develop resistance, thus necessitating novel treatment strategies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are a well-tolerated class of drugs that target tumors with defective DNA repair pathways. Interestingly, we previously reported that HER2+ breast cancer cells are sensitive to PARPi alone both in vitro and in vivo independent of a basal or induced DNA repair defect (Nowsheen et al., Cancer Research 2012). Further, we found that attenuation of NF-κB signaling may account for this intriguing susceptibility. To further substantiate the potential utility of PARPi in HER2+ breast cancer, we investigated the expression and cellular location of PARP and phospho-p65, indicators of activity of the PARP and NF-κB pathways, respectively, in human HER2+ breast cancer specimens and compared to HER2- breast tumors. Methods: Breast cancer patients treated at UAB with available stored tissue blocks between the years 1999 and 2012 were identified. Formalin-fixed, paraffin-embedded tissue blocks were stained for PARP and phospho-p65 and evaluated independently by two blinded physicians, including a board-certified pathologist. An H-score was calculated by multiplying the percent of tumor cells with staining intensity of 0, 1, 2, and 3+ and subsequently adding these together for a final score of 0-300. Nuclear and cystosolic staining were scored separately for both proteins. The number of samples with 2 or 3+ staining of PARP or phospho-p65 in each group was also assessed. Results: Forty-one HER2+ and 32 HER2- cases were examined. PARP and phospho-p65 were found to be almost exclusively nuclear in both groups. The mean H-score for nuclear PARP was 122.3 in HER2+ cases compared to 61.6 in HER2- cases (p value Conclusions: Our study suggests that HER2+ breast cancers have elevated markers for PARP and NF-κB activity compared to HER2- cancers. A direct correlation between PARP and phospho-p65 levels was also found. Furthermore, staining of ≥2+ for either protein was significantly different between the two groups suggesting this as a potential biomarker for clinical application. When combined with our previously published preclinical findings, the current research supports the potential clinical utility of PARPi in patients with this aggressive form of breast cancer. Citation Format: Lisa Klepczyk, Shi Wei, Jason Brazelton, Kimberly Keene, Yufeng Li, James Bonner, Andres Forero, Albert LoBuglio, William Grizzle, Eddy Yang. Increased expression of poly (ADP-ribose) polymerase (PARP) and phospho-p65 in human HER2+ breast cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B37.

Abstract P5-17-07: Influence of bevacizumab on local-regional recurrence in triple negative breast cancer

Background: Triple negative breast cancer (TNBC) comprises 15–20% of newly diagnosed invasive breast cancers and has been associated with an elevated risk of both local-regional recurrence (LRR) as well as distant failure. Bevacizumab (BEV) has been shown to improve pathologic complete response rates in the setting of neoadjuvant chemotherapy (NCT), but its effect on LRR remains undefined. This study reports the impact of adding BEV to standard breast cancer therapy in TNBC patients treated at a single institution. Methods: One hundred and eighty-five consecutive TNBC patients treated at the University of Alabama Birmingham from May 2005 to August 2010 were reviewed. Thirty-one TNBC patients treated with chemotherapy (CT) and BEV on prospective studies were matched (1:2) with 62 TNBC patients treated with CT alone, controlling for age, stage, and use of radiation (RT). The Kaplan-Meier method was used to estimate LRR, distant metastasis-free survival (DMFS), and overall survival (OS), and cohorts were compared using Cox proportional hazards models and the 2-sided log-rank test. Results: Mean age was 47 and 46 years in the cohorts with and without BEV, respectively. Stage in each cohort was as follows: 32% stage I, 61% stage II, and 7% stage III. Use of adjuvant RT was 81% in each cohort (25/31 BEV, 50/62 no BEV). BEV was delivered with NCT in 17 patients (55%) and with adjuvant CT in the remaining 14 patients (45%). Eleven patients (35%) completed an additional 1 year of maintenance therapy with BEV. LRR occurred in 2 (6%) patients treated with BEV vs. 16 (26%) treated with CT alone (HR = 0.25, 95% CI 0.06–1.07, p = 0.04). Distant recurrence occurred in 3 (10%) patients treated with BEV vs. 11 (18%) patients in the CT group HR=0.6, 95% CI 0.2–1.8, p = 0.48). There were 2 (6%) deaths in the BEV group vs. 12 (19%) in the CT alone group (HR = 0.55, 95% CI 0.13–2.3, p = 0.19). Conclusions: In a matched-pair analysis of TNBC patients, the addition of BEV to conventional breast cancer management was associated with a reduction in LRR. Further prospective study is necessary to examine the impact of BEV on local-regional control in TNBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-07.

Abstract P6-07-37: Impact of body mass index on recurrence risk in patients with ductal carcinoma in situ.

Background: Body mass index (BMI) has been correlated with risk of recurrence in invasive breast cancer, but the association between BMI and recurrence in ductal carcinoma in situ (DCIS) is less clear. Recent retrospective data indicates that local recurrence is not related to BMI at initial diagnosis. Here we examine the relationship between initial BMI and recurrence in a separate cohort of patients with DCIS. Methods: One hundred eighty-nine patients with DCIS treated between the years of 1999 and 2005 at the University of Alabama at Birmingham were analyzed. BMI was divided into 4 categories as follows: underweight (BMI Results: There were 199 cases of DCIS identified in our cohort of 189 patients (10 patients had bilateral disease). Of these 189 patients, 1.1% (2/189) were underweight, 31.2% (59/189) were normal weight, 22.7% (43/189) were overweight, and 21.7% (41/189) were obese. BMI could not be obtained for 23.3% (44/189) of patients. With a median follow-up of 87.2 months, there were 28 total recurrences identified in the 199 cases (14.1%) with 85.7% of these including a local recurrence. No significant associations were found between the likelihood of overall or local recurrence and any of the four BMI categories. Further, analysis of recurrence-free survival did not show any significant associations between BMI and recurrence. Conclusions: Our data supports recently reported evidence that BMI at diagnosis does not affect the risk of overall or local recurrence in patients with DCIS. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-37.