Towards precision radiation oncology: endocrine therapy response as a biomarker for personalization of breast radiotherapy.

Targeted therapies, such as endocrine therapies (ET), can exert selective pressure on cancer cells and promote adaptations that confer treatment resistance. In this study, we show that ET resistance in breast cancer drives radiation resistance through reprogramming of DNA repair pathways. We also show that pharmacological bromodomain and extraterminal domain inhibition reverses pathological DNA repair reprogramming in ET-resistant breast tumors and overcomes resistance to radiation therapy.

Feasibility and efficacy of active breathing coordinator assisted deep inspiration breath hold technique for treatment of locally advanced breast cancer.

BACKGROUND: Active breathing coordinator (ABC)-assisted deep inspiration breath hold (DIBH) is an important organ sparing radiation therapy (RT) technique for left-sided breast cancer patients. Patients with advanced breast cancer undergoing chest wall and regional nodal irradiation often require a field matching technique. While field matching has been demonstrated to be safe and effective in free breathing patients, its safety and accuracy in DIBH/ABC use has not been previously reported. PURPOSE: To report the accuracy, feasibility, and safety of field matching with ABC/DIBH for patients receiving breast/chest wall irradiation with nodal irradiation using a three-field technique. METHODS: From December 2012 to May 2018, breast cancer patients undergoing ABC/DIBH-based RT at a single institution were reviewed. For each fraction, the amount of overlap/gap between the supraclavicular and the tangential field were measured and recorded. Patient characteristics, including acute and delayed skin toxicities, were analyzed. RESULTS: A total of 202 patients utilized ABC/DIBH and 4973 fractions had gap/overlap measurements available for analysis. The average gap/overlap measured at junction was 0.28 mm ± 0.99 mm. A total of 72% of fractions had no measurable gap/overlap (0 mm), while 5.6% had an overlap and 22.7% a gap. There was no significant trend for worsening or improvement of gap/overlap measurements with increasing fraction number per patient. OSLD measurements were compared to the planned dose. The median dose 1 cm above the junction was 106% ± 7% of planned dose (range 94%-116%). One centimeter below the junction, the median dose was 114% ± 11% of planned dose (range 95%-131%). At the junction, the median dose was 106% ± 16.3% of planned dose (range 86%-131%). Acute skin toxicity was similar to historically reported values (grade 3, 5.4%, grade 4, 0%). CONCLUSION: ABC-assisted DIBH is a safe and technically feasible method of delivering RT in the setting of complex matching field technique for breast and regional nodal treatments.

A How-To Compendium for GammaPod Treatments, Clinical Workflow, and Clinical Program at an Early Adopting Institution.

In 2019, our institution became the second in the world to go live with GammaPod (Xcision Medical Systems, LLC, Columbia, MD), a device dedicated for stereotactic radiation therapy of breast cancer, with breast immobilization, real-time imaging, and highly-conformal dosimetry. At our institution, GammaPod is used for 5-fraction adjuvant partial breast irradiation, single-fraction tumor cavity boost before whole-breast irradiation, single-fraction preoperative radiation, and (in poor surgical candidates), single-fraction definitive radiation. Here, we describe our workflow, observed procedure step times, and homegrown techniques for improved efficiency in our institutional experience of 93 patients treated between 2019 and 2021.

Preliminary Results of Multi-Institutional Phase 1 Dose Escalation Trial Using Single-Fraction Stereotactic Partial Breast Irradiation for Early Stage Breast Cancer.

PURPOSE: We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. METHODS AND MATERIALS: Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size <3 cm treated with lumpectomy were enrolled in this phase 1 single-fraction S-PBI dose-escalation trial. Women received either 22.5, 26.5, or 30 Gy in a single fraction using a robotic stereotactic radiation system. The primary outcome was to reach tumoricidal dose of 30 Gy in a single fraction to the lumpectomy cavity without exceeding the maximum tolerated dose. Secondary outcomes were to determine dose-limiting toxicity and cosmesis. Tertiary goals were ipsilateral breast recurrence rate, distant disease-free interval, recurrence-free survival, and overall survival. RESULTS: From June 2016 to January 2021, 11, 8, and 10 patients were treated to doses of 22.5, 26.5, or 30 Gy in a single fraction, respectively, with median follow-up being 47.9, 25.1, and 16.2 months. No patients experienced acute (<90 days) grade 3 or higher treatment-related toxicity, and maximum tolerated dose was not reached. There were 2 delayed grade 3 toxicities. Four patients (13.8%) developed fat necrosis across all 3 cohorts, which compares favorably with results from other PBI trials. No dose cohort had a statistically significant cosmetic detriment from baseline to 12 months or 24 months follow-up by patient- or physician-reported global cosmetic scores. There were no reports of disease recurrence. CONCLUSIONS: This phase 1 trial demonstrates that S-PBI can be used to safely escalate dose to 30 Gy in a single fraction with low toxicity and without detriment in cosmesis relative to baseline.

Long-term Outcome of Prostate Cancer Patients Who Exhibit Biochemical Failure Despite Salvage Radiation Therapy After Radical Prostatectomy.

OBJECTIVES: Salvage radiation therapy (SRT) is an effective treatment for recurrent prostate cancer (PCa) after radical prostatectomy. We report the long-term outcome of men who developed biochemical recurrence (BCR) after SRT and were treated >14 years ago. METHODS: In total, 61 patients treated with SRT from 1992 to 2000 at our institution were identified. Survival was calculated by Kaplan-Meier method. Log-rank test and Cox regression were used to determine significance of clinical parameters. RESULTS: The median follow-up was 126 months (interquartile range, 66-167 mo). Thirty-four (56%) had prostate-specific antigen (PSA) failure after SRT. At 10 years, overall survival (OS) was 67%, freedom from PSA failure (FFPF) was 33%, prostate cancer-specific survival (PCSS) was 84%, and distant metastases-free survival (DMFS) was 84%. Pathologic T-stage, Gleason score, seminal vesicle involvement, and pre-SRT PSA were associated with FFPF. For patients who failed SRT, the median time to BCR after SRT was 30 mo. A total of 19 (68%) received androgen deprivation therapy. The median OS was 13.6 years. At 10 years from time of BCR, OS was 59%, PCSS was 73%, DMFS was 75%, and castration-resistant-free survival was 70%. Early SRT failure correlated with significantly decreased DMFS and PCSS. Ten-year DMFS from SRT was 43% (BCR≤1 y) versus 91% (BCR>1 y). CONCLUSIONS: Extended follow-up demonstrates that despite SRT failure, PCSS remains high in select patients. Early failure (≤1 y after SRT) predicted for significantly worse outcome and may represent a subgroup with more aggressive disease that may be considered for further prospective clinical studies.

Early and multiple PSA bounces can occur following high-dose prostate stereotactic body radiation therapy: Subset analysis of a phase 1/2 trial.

PURPOSE: We hypothesized that high-dose stereotactic body radiation therapy (SBRT) would lead to faster time to nadir and lower nadir values compared with conventional radiation therapy experiences. We now report prostate-specific antigen (PSA) kinetics following high-dose SBRT in patients treated with radiation alone. METHODS AND MATERIALS: Ninety-one patients were enrolled on the phase 1/2 dose escalation study of SBRT for localized prostate cancer. All patients with at least 36 months of follow-up and without hormone therapy were included in this analysis (n = 47). Treatment response parameters evaluated include time to nadir, nadir value, occurrence of PSA bounces (rise of ≥0.2 ng/mL followed by a subsequent fall), magnitude of bounces, duration of bounces, and correlation of bounces with clinical outcomes. RESULTS: Median follow-up was 42 months (range, 36-78 months). Treatment dose levels were 45 Gy (n = 10), 47.5 Gy (n = 8), and 50 Gy (n = 29) in 5 fractions. Biochemical control rate was 98%. Median PSA at follow-up was 0.10 ± 0.20 ng/mL. Median time to nadir was 36 ± 11 months. A total of 24/47 (51.1%) patients had ≥1 PSA bounce. Median magnitude of PSA rise during bounce was 0.50 ± 1.2 ng/mL. Median time to first bounce was 9 ± 7.0 months. Median bounce duration was 3 ± 2.3 months for the first bounce and 6 ± 5.2 months for subsequent bounces. Prostate volumes <30 mL were associated with a decreased likelihood of bounce (P = .0202), and increasing prostate volume correlated with increasingly likelihood of having ≥2 bounces (P = .027). Patients reaching PSA nadir of ≤0.1 ng/mL were less likely to experience any bounce (P = .0044). CONCLUSIONS: Compared with other SBRT experiences, our study demonstrated a higher PSA bounce rate, a similar or shorter median time to bounce, and a very low nadir. Prostate volume appears correlated with bounce.

Personalized Combined Modality Therapy for Locally Advanced Non-small Cell Lung Cancer.

Locally advanced non-small cell lung cancer (NSCLC) is a heterogeneous disease, and we have embarked on an era where patients will benefit from individualized therapeutic strategies based on identifiable molecular characteristics of the tumor. The landmark studies demonstrating the importance of molecular characterization of tumors for NSCLC patients, the promising molecular pathways, and the potential molecular targets/agents for treatment of this disease will be reviewed. Understanding these issues will aid in the development of rationally designed clinical trials, so as to determine best means of appropriately incorporating these molecular strategies, to the current standard of radiation and chemotherapy regimens, for the treatment of locally advanced NSCLC.

DAB2IP regulates autophagy in prostate cancer in response to combined treatment of radiation and a DNA-PKcs inhibitor.

Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol 3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G(2)/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More significantly, we found that DAB2IP-deficient PCa cells show dramatic induction of autophagy after treatment with radiation and NU7441. However, restoring DAB2IP expression in PCa cells resulted in decreased autophagy-associated proteins, such as LC3B and Beclin 1, as well as decreased phosphorylation of S6K and mammalian target of rapamycin (mTOR). Furthermore, the presence of DAB2IP in PCa cells can lead to more apoptosis in response to combined treatment of NU7441 and ionizing radiation. Taken together, NU7441 is a potent radiosensitizer in aggressive PCa cells and DAB2IP plays a critical role in enhancing PCa cell death after combined treatment with NU7441 and radiation.