Kevin K. Lin

Acute and Chronic Complications in Breast Cancer Patients Treated with Intraoperative Radiation Therapy

Introduction Intraoperative radiation therapy (IORT) permits the delivery of radiation therapy directly to the tumor bed at the time of surgery. Minimal data are available about the complications associated with this modality of treatment using the Xoft® Axxent Electronic Brachytherapy (Axxent) System.MethodsA total of 702 patients who received IORT using the Xoft® Axxent System at Hoag Memorial Hospital Presbyterian between June 2010-February 2016 were accrued in an IORT data registry study. The prospective and retrospective protocols were approved by the institutional review board and met the guidelines of their responsible governmental agency. Data were collected at 1xa0week, 1xa0month, 3xa0months, 6xa0months, 1xa0year, and thereafter yearly. Acute complications were defined as those occurring within the first month. Chronic complications were those that persisted beyond 6xa0months.Results Acute complications were observed in 21xa0% of patients and included hematomas that required drainage, seromas requiring drainage more than 3 times, infections treated with antibiotics or surgery, necrosis requiring surgery, and erythema. Chronic complications were observed in 13xa0% of patients and included seromas, fibrosis, and hyperpigmentation. The majority of acute and chronic problems from IORT were mild. If grade I erythema, fibrosis, and hyperpigmentation were removed, only 32 of 702 (4.6xa0%) had significant complications. Our complication rates were comparable to those of the TARGIT trial.ConclusionsIORT is a modality that safely delivers radiation therapy to patients diagnosed with breast cancer. This technique allows women who cannot (or decline to) undergo whole breast radiation to consider breast-conserving therapy rather than mastectomy.

Intraoperative Radiation Using Low-Kilovoltage X-Rays for Early Breast Cancer: A Single Site Trial

IntroductionTwo prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy (IORT) to be a safe alternative to whole breast radiation therapy following breast-conserving surgery for selected low-risk patients. However, minimal data are available about the clinical effectiveness of this modality of treatment using the Xoft® Axxent® Electronic Brachytherapy (eBx®) System®.MethodsA total of 201 patients with 204 early-stage breast cancers were enrolled in a prospective X-ray IORT trial from June 2010 to September 2013. All tumors were treated with breast-conserving surgery and IORT. Data were collected at 1xa0week, 1xa0month, 6xa0months, 1xa0year, and yearly thereafter.ResultsWith a median follow-up of 50xa0months, there have been seven ipsilateral breast tumor events (IBTE), no regional or distant recurrences, and no breast cancer-related deaths. One IBTE was within the IORT field, four outside of the IORT field but within the same quadrant as the index cancer, and two were new biologically different cancers in different quadrants. Three events were in patients who deviated from the protocol criteria. Kaplan–Meier analysis projects that 2.9% of patients will recur locally at 4xa0years.ConclusionsRecurrence rates observed in this trial were comparable to those of the TARGIT-A and ELIOT trials as well as the retrospective TARGIT-R trial. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of IORT in selected women with low-risk breast cancer.

Acute and Chronic Complications in Patients with Ductal Carcinoma in Situ Treated with Intraoperative Radiation Therapy

Intraoperative radiation therapy (IORT) delivers radiation therapy directly to the tumor bed at the time of surgery. Minimal data are available regarding IORT complications in patients diagnosed with ductal carcinoma in situ (DCIS) using the Xoft® Axxent eBx® System. 146 patients with pure DCIS received X‐ray based IORT therapy using the Xoft® Axxent eBx® System at Hoag Memorial Hospital Presbyterian between June 2010 to April 2016 and were accrued to an IORT data registry study. The protocols were approved by the institutional review board and met the guidelines of their responsible governmental agency. Data were collected at 1 week, 1 month, 6 months, 1 year, and thereafter yearly. Acute complications were defined as those occurring within the first month. Chronic complications were those that persisted beyond 6 months. Acute complications were observed in 18% of patients and included hematomas that required drainage, an infection treated with antibiotics, and erythema. Chronic complications were observed in 12% of patients and included a seroma, fibrosis and hyperpigmentation. The majority of acute and chronic problems were mild (Grade I). If Grade I erythema, fibrosis, and hyperpigmentation are not included, only 11/146 patients (7.5%) had significant complications. The rate of acute and chronic complications from X‐ray IORT in DCIS patients was low compared to historical toxicity rates observed in DCIS patients treated with whole breast irradiation. Our data indicate that X‐ray IORT can be utilized safely in patients diagnosed with DCIS.

Intraoperative Radiation Therapy (IORT): A Series of 1000 Tumors

BackgroundTwo prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy to be a safe alternative, with a low-risk of local recurrence, compared with whole breast radiation therapy, following breast-conserving surgery, for selected low-risk patients. We report the first 1000 tumors treated with this modality at our facility.MethodsA total of 1000 distinct breast cancers in 984 patients (16 bilateral) were treated with breast conserving surgery and X-ray IORT from June 2010 to August 2017. Patients were enrolled in an IORT registry trial. Local recurrence was the primary endpoint.ResultsThere have been 28 ipsilateral local recurrences, ten DCIS and 18 invasive. Four local recurrences were within the IORT field, 13 outside of the IORT field but within the same quadrant as the index cancer, and 11 were new cancers in different quadrants. There have been four regional nodal recurrences and one distant recurrence. There have been no breast cancer related deaths and 14 non-breast cancer deaths. With a median follow-up of 36xa0months, Kaplan–Meier analysis projects 3.9% of patients will recur locally at 4xa0years. This includes all ipsilateral events in all quadrants.ConclusionsThe local, regional, and distant recurrence rates observed in this trial were comparable to those of the prospective randomized TARGIT-A and ELIOT trials. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of X-ray IORT in women with low-risk breast cancer.

Abstract AP27: FEASIBILITY OF MONITORING RESPONSE TO THE PARP INHIBITOR RUCAPARIB WITH TARGETED DEEP SEQUENCING OF CIRCULATING TUMOR DNA (CTDNA) IN WOMEN WITH HIGH GRADE OVARIAN CARCINOMA ON THE ARIEL2 TRIAL

BACKGROUND:TP53 mutations are present in >97% cases of high-grade serous ovarian cancer (HGSOC). Detection of TP53 mutations in ctDNA extracted from plasma has the potential to monitor disease course and treatment response. We have developed targeted amplicon deep sequencing (TADS) to detect low frequency mutations throughout the TP53 gene in ctDNA. Rucaparib is a PARP inhibitor in development for treatment of tumors with HR pathway deficiency. We used TADS to assess TP53 mutant allele fraction (MAF) in ctDNA from patients in ARIEL2, a phase 2 study of rucaparib for treatment of relapsed high-grade ovarian cancer (NCT01891344). MATERIAL AND METHODS: Plasma samples (n=65) from 18 patients were collected during screening, on day 1 of each cycle, and at the end of rucaparib treatment. DNA extracted from plasma underwent TADS of TP53 (median depth 6916×). FFPE tumor specimens were profiled using an NGS-based assay with a targeted gene panel including TP53. Investigator-assessed clinical response rates were evaluated by RECIST v1.1 and GCIG CA-125 criteria. RESULTS: Concordant TP53 mutations were detected in tumor and ctDNA from plasma for all 18 patients. Median TP53 MAF at screening and cycle 1 day 1 was 5.1% (interquartile range: 1.1–17.5, n=16) and 3.8% (IQR: 0.68–10.3, n=16), respectively. Fourteen patients were evaluable for response measured by quantification of TP53 MAF between cycle 1 and 2 (missing sample: n=2; TP53 MAF 50% reduction of TP53 MAF in ctDNA at cycle 2 achieved a RECIST confirmed PR (see Table); this included 5/6 patients with either a germline or somatic mutation in BRCA1/BRCA2. No patients with CONCLUSIONS: Noninvasive detection of TP53 mutations by TADS is feasible, using plasma samples collected from women with relapsed platinum-sensitive high-grade ovarian cancer participating in an international multicenter trial. Circulating tumor DNA is a promising biomarker for monitoring response to the PARP inhibitor rucaparib. We are now testing the pre-specified hypothesis that a >50% reduction in TP53 MAF between baseline and cycle 2 is predictive of response to rucaparib using 560 plasma samples from 139 ARIEL2 subjects. Updated results will be presented at the meeting. Citation Format: Anna Piskorz, Kevin K. Lin, James Morris, Elaina Mann, Amit Oza, Robert L. Coleman, David M. O9Malley, Michael Friedlander, Janiel M. Cragun, Ling Ma, Heidi Giordano, Nitzan Rosenfeld, Mitch Raponi, Iain A. McNeish, Elizabeth Swisher, James D. Brenton. FEASIBILITY OF MONITORING RESPONSE TO THE PARP INHIBITOR RUCAPARIB WITH TARGETED DEEP SEQUENCING OF CIRCULATING TUMOR DNA (CTDNA) IN WOMEN WITH HIGH GRADE OVARIAN CARCINOMA ON THE ARIEL2 TRIAL [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP27.

Abstract 4676: DNA repair protein expression and response of homologous recombination deficient ovarian cancer to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in the ARIEL2 Part 1 study

Background: PARP inhibitors (PARPis) are active in cancers with homologous recombination (HR) defects. Preclinical studies have shown that secondary mutations or alterations in gene expression (e.g., downregulation of 53BP1, Ku70, Ku80 or DNA-PKcs) restore HR and confer PARPi resistance. In addition, low PARP1 expression can diminish PARP trapping and cause PARPi resistance. ARIEL2 Part 1 is a phase 2 study of the PARPi rucaparib in platinum sensitive, relapsed high grade serous or endometrioid ovarian cancer (OC). Pretreatment OC biopsies were previously assayed for HR gene mutations and loss of heterozygosity (LOH), a genomic scar that reflects HR deficiency. Two tumor groups (BRCA wildtype [wt]/LOH high and BRCA1 or BRCA2 mutant) have objective response rates of 29.3% and 80%, respectively, as well as progression free survival (PFS) of 5.7 and 12.8 months, respectively, on rucaparib (E. Swisher et al., Lancet Oncol., in press). Common AEs included nausea (80%), asthenia/fatigue (78%), constipation (46%), and vomiting (44%). The present studies tested the hypotheses that i) lower PARP1 expression and/or ii) lower expression of NHEJ components 53BP1, DNA-PKcs, Ku80, Ku70, or LIG4, may correlate with diminished response rate as well as PFS in pts treated with rucaparib on ARIEL2. Methods: Immunohistochemical assays were developed for 53BP1, DNA-PKcs, Ku80, Ku70, LIG4, and PARP1 and validated in formalin fixed, paraffin embedded cell lines differing in analyte expression. Available pretreatment OC biopsies from ARIEL2 Part 1 were stained and scored for % of tumor nuclei that were negative (0), weak (1+), moderate (2+) or strong (3+). Modified H-scores were correlated with clinical characteristics and outcome measures. Results: Pretreatment biopsies from 62-68 pts were successfully stained for each repair protein. Across the samples, PARP1 H-scores varied from 0 to 300 (median 160). Focusing on the BRCA wt/LOH high group (n = 38), there was no significant difference in PFS of pts with low ( 200) PARP1 H-score (p = 0.57). Expression of DNA-PKcs, Ku70, Ku80, and LIG4 was generally lower (median H-scores 20-60) and did not individually correlate with response or PFS. In contrast, there was a trend toward improved PFS in BRCA wt/LOH high OC pts expressing intermediate or high 53BP1 (H-score ≥ 100, n = 10) compared to pts with low 53BP1 (H-score Conclusions: In the BRCA wt/LOH high group, pretreatment PARP1 expression does not correlate with rucaparib response. In contrast, BRCA wt/LOH high OC pts with low 53BP1 have a trend toward shorter PFS with rucaparib, suggesting that 53BP1 downregulation might correlate with clinical PARPi resistance in BRCA wt/LOH high OC. Citation Format: Andrea E. Wahner Hendrickson, Kevin K. Lin, Daniel W. Visscher, Rachel M. Hurley, Mitch Raponi, Thomas C. Harding, Linda M. Murphy, Jill M. Wagner, Heidi Giordano, Iain McNeish, Elizabeth M. Swisher, Scott Kaufmann. DNA repair protein expression and response of homologous recombination deficient ovarian cancer to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in the ARIEL2 Part 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4676. doi:10.1158/1538-7445.AM2017-4676