Corbin, Kimberly S.

Abstract Objective Patients with hormone receptor positive (HR+), HER2- metastatic breast cancer frequently require radiation therapy (RT) in addition to systemic therapy for disease control and symptom management. CDK 4/6 inhibitors are increasingly used in the care of hormone positive breast cancers. Stereotactic body radiotherapy (SBRT), a form of very focused high dose radiation, is also increasingly used in the care of metastatic breast cancer. Limited data have reported on the safety of palliative RT with CDK4/6 inhibitors, with some reports demonstrating synergistic effects with potential for increased toxicity. The objective of our study is to assess toxicity among patients who received SBRT, stereotactic radiosurgery (SRS), or other high dose RT along with CDK 4/6 inhibitors for treatment of metastatic breast cancer. Methods Women with metastatic breast cancer who received SBRT, SRS, or other higher dose RT with CDK 4/6 inhibitors at any point in their treatment between 2013 and 2021 were retrospectively identified. Timing of radiation therapy, either before, during, or after CDK 4/6 inhibitor use was assessed, as well as the interval between the two treatments. Treatment sites for radiotherapy included lung/chest, spine, and brain metastases. Physician assessed adverse events were obtained through clinical follow up and graded using CTCAE v5. Local control and OS were reported. Results Twenty patients met study inclusion criteria. Patients received radiation therapy and CDK 4/6 inhibitors concurrently (within 7 days) [n=7, 35%], within 30 days (RT pre-CDK 4/6 inhibitor use) [n=3, 15%], and greater than 30 days (RT pre-CDK 4/6 inhibitor use [n=6, 30%] and RT post-CDK 4/6 inhibitor use [n=4, 20%]). Radiation treatment sites were spine [n=10, 55%], brain [n=6, 30%], and lung/chest wall [n=3, 15%]. Radiation doses were as follows: 60 Gy in 5 fractions [n=1, 5%], 50 Gy in 5 fractions [n=2, 10%], 55 Gy in 20 fractions (chest wall recurrence) [n=1, 5%], 35 Gy in 15 fractions [n=1, 5%], 30 Gy in 10 fractions [n=6, 30%], 30 Gy in 3 fractions [n= 4, 20%], 24 Gy in 1 fraction [n=3, 15%], 20 Gy in 5 fractions [n=2, 10%]. Palbociclib was used in 85% of patients [n=17] and abemaciclib in 15% [n=3]. Median follow up for surviving patients was 4.7 years [IQR: 2.5-6.8 years]. Local control was achieved in 85% of patients [n=17]. Median OS was 2.7 years [IQR: 0.1-6.8 years]. Grade 2 toxicity [n=9, 45%] and grade 3 toxicity [n=3, 15%] was reported across all three treatment areas, with grade 2 or 3 fatigue [n=7, 35%] being the most frequently reported toxicity. In the spine treatment group, 1 patient who had CDK 4/6 inhibitor use within 30 days of radiotherapy experienced a grade 3 vertebral compression fracture as well as grade 3 fatigue. In the lung/chest wall treatment group, the patient treated to 55 Gy in 20 fractions to the chest wall with concurrent use had grade 3 skin/wound toxicity requiring prolonged wound care before healing. In the intra-cranial SRS group, grade 3 fatigue was reported in 1 patient with concurrent use. Conclusion The use of CDK 4/6 inhibitors concurrently with or within 30 days of radiation therapy was generally well tolerated with limited grade 3 toxicity. Two of three reports of grade 3 toxicity occurred with concurrent treatment. Due to the potential radiosensitizing properties of CDK 4/6 inhibitors, it may be prudent to hold combined treatment when clinically feasible. Further study is needed to validate these results. Citation Format: Kiran Chauhan, Roman O. Kowalchuk, Allison E. Garda, Dean A. Shumway, Mark R. Waddle, Robert Mutter, Kimberly Corbin. Safety of stereotactic body radiation therapy, stereotactic radiosurgery, and other radiation therapy with use of CDK 4/6 inhibitors for hormone receptor positive (HR+), HER2- metastatic breast cancer: a retrospective cohort study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-05.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

AbstractBackgroundThe objective of this study was to report acute changes in patient‐reported quality of life (PRQOL) using the 26‐item Expanded Prostate Index Composite (EPIC‐26) questionnaire in a prospective study using hypofractionated intensity‐modulated proton beam therapy (H‐IMPT) targeting the prostate and the pelvic lymph nodes for high‐risk or unfavorable intermediate‐risk prostate cancer.MethodsFifty‐five patients were enrolled. H‐IMPT consisted of 45 GyE to the pelvic lymph nodes and 67.5 GyE to the prostate and seminal vesicles in 25 fractions. PRQOL was assessed with the urinary incontinence (UI), urinary irritative/obstructive symptoms (UO), and bowel function (BF) domains of EPIC‐26 questionnaire. Mean changes in domain scores were analyzed from pretreatment to the end of treatment and 3 months posttreatment. A clinically meaningful change (or minimum important change) was defined as a score change > 50% of the baseline standard deviation.ResultsThe mean scores of UO, UI, and BF at baseline were 84.6, 91.1, and 95.3, respectively. At the end of treatment, there were statistically significant and clinically meaningful declines in UO and BF scores (−13.5 and −2.3, respectively), while the decline in UI score was statistically significant but not clinically meaningful (−13.7). A clinically meaningful decline in UO, UI, and BF scores occurred in 53.5%, 22.7%, and 73.2% of the patients, respectively. At 3 months posttreatment, all three mean scores showed an improvement, with fewer patients having a clinically meaningful decline in UO, UI, and BF scores (18.4%, 20.5%, and 45.0%, respectively). There was no significant reduction in the mean UO and UI scores compared to baseline, although the mean BF score remained lower than baseline and the difference was clinically meaningful.ConclusionsUO, UI, and BF scores of PRQOL declined at the end of H‐IMPT. UO and UI scores showed improvement at 3 months posttreatment and were similar to the baseline scores. However, BF score remained lower at 3 months posttreatment with a clinically meaningful decline.

Abstract Background: Partial breast irradiation (PBI) is an established option for selected patients with early stage breast cancer. The optimal technique, target volume and dose/fractionation for PBI has yet to be defined. The most studied regimen in North America (38.5 Gy in 10 fractions twice daily) has been associated with cosmetic deterioration. We hypothesized that condensing treatment and reducing the total administered dose could improve the therapeutic ratio in luminal breast cancer and DCIS based on emerging evidence that breast cancer is more sensitive than surrounding normal tissues to high dose fractions. Herein, we report cosmetic, tolerability, disease control, and patient reported outcomes of a novel ultra-accelerated PBI regimen. Methods: We conducted a single arm, three cohort trial of photon, proton, and brachytherapy PBI. Technique was selected at physician and patient discretion. Eligible women were age ≥ 50 years with estrogen receptor positive (ER+), sentinel lymph node negative invasive or in-situ breast cancer measuring ≤ 2.5 cm. The regimen was designed to have comparable biologically equivalent effect as 40 Gy in 15 fractions, assuming an α/β ratio of 3.5. Intracavitary brachytherapy target volume was lumpectomy cavity plus 1 cm and prescribed 21 Gy in 3 fractions. Photon and proton target volumes were post-operative tumor bed plus 1 cm and a 3 mm setup uncertainty margin, prescribed 21.9 Gy (RBE) in 3 fractions, and delivered with image guidance. The primary outcome was the percentage difference in patients with adverse cosmesis (defined as fair or poor cosmesis) at 3 years compared to baseline pre-PBI, as assessed by trained nurses using the 4-point Harvard breast cosmesis scale. Patients also completed quality of life surveys and self-reported cosmesis using the 4-point scale. Locoregional and distant recurrence-free survival was determined using the Kaplan-Meier method. Adverse events were assessed using CTCAE, v 4.0. Results: Between 2015 and 2017, 163 patients were treated: photons in 58, protons in 48, and brachytherapy in 57. Median patient age was 66 years. 129 (79%) patients had invasive breast cancer (all ER+) and 34 (21%) had DCIS (83% ER+). Median tumor size was 1.1 cm. Grade was 2-3 in 102 (63%). The median mean heart/ipsilateral lung doses were photons 0.1/1.6 Gy, protons <0.001/0.1 Gy, and brachytherapy 0.5/0.9 Gy. Median follow-up was 4.1 years (IQR 3.9-5.0). The proportion of patients with adverse cosmesis (by RN assessment) was 14.3% at baseline and 3.8% at 3 years, with four patients (1 photon, 1 proton, 2 brachytherapy) experiencing cosmetic deterioration at 3 years from baseline. The proportion with adverse cosmesis by self-report at 3 years was 2.4%, with three patients (1 photon, 1 proton, 1 brachytherapy) reporting cosmetic deterioration. Four patients developed locoregional recurrence (1 photons, 2 protons, 1 brachytherapy); three were local only and one was local and distant. 4-year locoregional recurrence and distant metastasis-free survival were 97.9% and 97.4%, respectively. There were 2 treatment related ≥ grade 2 late events (grade 2 fibrosis and grade 2 seroma, both brachytherapy associated), and no evidence of deterioration in patient-reported pain, fatigue, breast related or overall quality of life, as assessed by the patient reported outcomes version of the CTCAE, 10-point linear analog scales, and the breast cancer treatment outcomes scale. Conclusions: Ultra-accelerated 3-fraction PBI exquisitely spared normal tissues and was associated with favorable cosmetic outcomes, disease control, and excellent long-term tolerability. This ‘precision-radiotherapy’ approach may optimize the therapeutic ratio over more aggressive radiotherapy options as well as radiotherapy omission, particularly in patients with long life expectancies. Citation Format: Robert Mutter, Tina Hieken, Todd DeWees, Arslan Afzal, Stephanie Kenison, Laura Vallow, Christopher Deufel, Nicholas Remmes, Kathryn Ruddy, Judy Boughey, Keith Furutani, Amy Degnim, James Jakub, Tamara Vern-Gross, Dean Shumway, William Wong, Samir Patel, Lisa McGee, Minetta Liu, Carlos Vargas, Daniel Visscher, Bradley Stish, Deanna Pafundi, Mark Waddle, Michael Golafshar, Michele Halyard, Kimberly Corbin, Sean Park. Ultra-accelerated photon, proton, and brachytherapy partial breast irradiation: Primary results of the Mayo 3-fraction trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD7-03.

Particle therapy has received increasing attention in the treatment of breast cancer due to its unique physical properties that may enhance patient quality of life and reduce the late effects of therapy. In this review, we will examine the rationale for the use of proton and carbon therapy in the treatment of breast cancer and highlight their potential for sparing normal tissue injury. We will discuss the early dosimetric and clinical studies that have been pursued to date in this domain before focusing on the remaining open questions limiting the widespread adoption of particle therapy.

Abstract Background Proton beam therapy (PBT) is a promising radiotherapeutic method by which the proton Bragg peak may be exploited to reduce the dose to non-target normal tissues, when compared with the conventional photon treatment (PhT). Purpose To evaluate the mechanical function of the left ventricle by endocardial longitudinal (GLS-basic strain), circumferential (GCS) and radial strain (GRS) and systolic (SRs) and early diastolic (SRe) strain rate following thoracic radiotherapy. Methods Between March 2016 and March 2017, 58 patients with breast or thoracic cancer scheduled to receive radiotherapy were enrolled prospectively and, underwent 2D-STE echocardiography with basic (GLS) and comprehensive (GCS, GRS,GLSRs, GCSRs, GRSRs, GLSRe, GCSRe, GRSRe parameters) analysis at pre-treatment, mid-treatment, end of treatment, 3 month and 1 year follow-up. LVEF was calculated by the biplane Simpson technique. Shapiro-Wilk's test was performed to evaluate the normal distribution of the data. Comparison between groups was performed with Student's t-test or Wilcoxon test for quantitative variables and with Chi-Square test or Fisher's exact test for qualitative variables. Tukey-Kramer method was used to compare means during follow up. A p-value <0.05 was assumed as the level of statistical significance. Results Mean age was 53.3±10.9 years and 91.3% were women. PBT was used to treat 38 patients; PhT in 20. The median of the mean heart dose was lower with PBT than PhT (79±92 vs 829±1121 cGy, respectively [P<.001]). No significant changes in LVEF or GLS for PBT or PhT were seen. Comprehensive strain analysis showed changes in endocardial longitudinal, radial, and circumferential early diastolic strain rate (SRe) in patients undergoing photon beam (PhT) up to one year of follow up (Table 1). No changes were detected in the PBT group. All other variables were non-significant (Not shown). Conclusion This is the first longitudinal study, with a one-year follow-up, that shows the relaxation properties of LV are compromised during PhT but not PBT. These findings should be followed in time to evaluate their influence on overall heart function. Funding Acknowledgement Type of funding sources: None. Table 1

Adenosquamous carcinoma of the breast is a rare subtype of metaplastic carcinoma, which accounts for <1% of invasive breast malignancy. Metaplastic carcinoma is usually high grade and aggressive with typically reported benign imaging features when compared to invasive ductal carcinoma. However, the adenosquamous variant is a subtype with a more favorable prognosis. Within the literature, there is limited imaging description with case studies focusing on metaplastic carcinoma. Herein, we report seven cases of the adenosquamous subtype describing the imaging findings with correlation to clinical history and pathology. The majority of patients (n = 6) presented with palpable breast masses. One patient was identified through screening mammography. Mammographically (n = 6), tumors appeared as irregular masses. Sonographically (n = 7), tumors appeared as irregular masses ranging from solid to mixed solid/cystic masses. On MRI (n = 1), one tumor appeared as an irregular rim enhancing mass. FDG PET/CT (n = 2) and whole-body bone scan (n = 1) were also available for review. The majority of tumors were low-grade (n = 6) with only one high-grade tumor. This case series of seven patients demonstrated predominantly suspicious imaging features despite the majority being low-grade tumors.

Abstract Background: DNIV accounts for 6%–10% of newly diagnosed breast cancer cases. Despite widespread mammography screening, its incidence is increasing in the United States and survival of this disease has only modestly improved since the late 1970s. As patient data accumulates in EHR, it’s promising to generate practice-based evidence through utilization of observational data sources. However, assembly of a DNIV cohort based on EHR data is challenging, as key pathologic and staging information are stored in unstructured clinical narratives and not available as structured data. In this study, we developed a rule-based algorithm to phenotype DNIV using natural language processing (NLP) techniques, and implemented the algorithm on our institutional EHR to extract potential DNIV cases. Methods and Results: We defined DNIV as those with either (1) M1 disease identified at time of initial presentation or M1 disease identified within 4 months after definitive surgery. We first developed a reference case list of DNIV verified by physician chart review of the EHR. We next refined the algorithm on a training dataset containing 51 positive and 38 negative reference cases. Next we tested the performance on the testing data containing 23 positive and 55 negative cases. The phenotyping algorithm identified key data elements using NLP, i.e., stage IV breast cancer, definitive surgery, stage 0-III, recurrent breast cancer and associated dates. To identify DNIV cases, phenotyping algorithm integrated temporal relations among the key data elements. The following steps were conducted in the following sequential order: (1) Identification of patients with breast cancer diagnosis using ICD-9 and ICD-10 codes. (2) Patients are positive cases if there are explicit mentions that delineate DNIV from recurrent metastatic breast cancer, such as “de novo stage IV” or “primary intact” detected by NLP at time of diagnosis. (3) Otherwise, patients with definitive surgery are selected if stage IV was within 5 years before definitive surgery or within 4 months after definitive surgery, along with patients with stage IV but without definitive surgery. (4) We further excluded patients with stage 0-III detected within 5 years after stage IV. (5) We further excluded patients with recurrent breast cancer detected before or at time of detection of stage IV. The remaining patients were left as positive cases. Precision of the algorithm was 70%, recall was 87% and F1, the weighted average of precision and recall, was 77%. We implemented our algorithm to interrogate 10 million clinical documents in a cohort of 56,548 patients with breast cancer diagnosis codes who presented to our institution between 2004 and 2018 and had research authorization. We identified 1918 potential DNIV cases. Conclusion: Our future focus is on algorithm refinement. An algorithm-generated cohort could serve as a data source for further study on outcomes related to DNIV and ideally as automated data abstractor and staging process. Citation Format: Liwei Wang, Karthik Giridhar, Kimberly Corbin, Brenda Ernst, Sadia Choudhery, Emmanuel Gabriel, Feichen Shen, Hongfang Liu, James Jakub. Identifying de novo stage IV breast cancer (DNIV) cases in Electronic Health Records (EHR) using natural language processing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-050.