Faculty Bibliography

The overall number of breast cancer patients at risk of developing local-regional disease recurrence has been increasing due to long-term survivorship from improvements in multimodality breast cancer treatment and a steady increase in breast cancer incidence. Many patients receive radiotherapy as part of definitive multidisciplinary breast cancer treatment, and to date, practitioners have approached reirradiation delivery with reticence due to concern for serious toxicities that may be incurred with high cumulative radiation doses. However, a subset of patients with breast cancer recurrence may benefit from reirradiation for improved locoregional tumor control. An emerging body of evidence has demonstrated promising efficacy and safety of breast cancer reirradiation that are gradually redefining the treatment paradigm. In addition, an increase in systemic therapy options has further optimized the opportunity for successful salvage of breast cancer recurrence. In this critical review, we review breast cancer radiation and systemic therapy salvage options, available data, ongoing studies, and treatment delivery considerations.

Outcomes for patients with early breast cancer have improved in recent years as detection and treatments have improved. The goal of many recent trials has therefore been to identify patients in whom de-intensification of therapy may be appropriate, thereby maximizing the therapeutic ratio of breast cancer treatments. In each discipline within breast cancer, surgery, radiation oncology, and medical oncology, trials have explored treatment de-escalation. In surgery, studies evaluate the omission of surgery to the breast or axilla; in radiation oncology, studies evaluate reduced dose and/or number of fractions (hypofractionation), reduced target [partial breast irradiation (PBI)], and omission of RT altogether; in medical oncology, studies evaluate reduced duration, alternate forms, and omission of ET altogether. In many cases, these studies have shown that targeted omission or de-intensification does not compromise outcomes. The challenge in multidisciplinary care is how to implement these deintensification strategies for a particular patient in relation to other aspects of the overall treatment plan. In this critical review, we review the data in support of omission or de-intensification of surgical, radiation, and endocrine therapies in patients with low risk breast cancer, and consider these approaches in relation to one another.

PURPOSE/OBJECTIVE:The prognosis and optimal treatment for microinvasive breast cancer is controversial with some data indicating a higher local recurrence with microinvasive disease as compared to early-stage invasive breast cancer. The goal of our study was to compare long-term outcomes between patients with T1mi disease and early-stage breast cancer after breast-conserving surgery and whole breast irradiation (WBI). METHODS:We reviewed all patients treated at our institution from 2013 to 2019 with T1mi-T2N0 disease. Cox proportional hazard model was used to find independent prognostic variables associated with local recurrence (LR). Survival curves were analyzed by Kaplan-Meier. RESULTS:We found 1155 patients with 56 (4.8%) having T1mi disease. The 5-year local recurrence rate was 5.3% in patients with T1mi disease and 1.2% in patients T1-2 disease (HR = 2.73; 95% CI 0.43, 17.9; p = 0.09). On Cox multivariate analysis, younger age, positive margins and the need for re-excision were prognostic for LR. Out of the 3 patients with microinvasive disease who developed a local recurrence, two had DCIS < 2 mm from the margin and the third patient underwent two re-excisions due to DCIS margins < 2 mm. CONCLUSIONS:Our study showed that patients with microinvasive disease treated with hypofractionated WBI had a numerically higher 5-year local recurrence rate than patients with T1a-2 disease though this difference was not statistically significant. Given the rarity of microinvasive disease, further work is needed to define optimal surgical and adjuvant management and to better clarify the risk of local recurrence in this patient population.

PURPOSE/OBJECTIVE:In patients with breast cancer, prone radiation therapy (RT) has been shown to reduce heart and lung dose. Though prone positioning is routinely used for whole breast RT, its use when treating the regional lymph nodes is not widespread. METHODS AND MATERIALS/METHODS:In this phase 1/2 trial for stage IB-IIA breast cancer treated with lumpectomy or mastectomy, patients received 40.5 Gy in 15 fractions to the breast or chest wall and regional lymph nodes with an integrated tumor bed boost for lumpectomy patients. Primary endpoints were grade >2 acute toxicity and dosimetric feasibility. Secondary endpoints were the incidence of resimulation to improve dosimetry and late toxicity. Exploratory endpoints were local recurrence, disease-free survival, distant recurrence-free survival, and overall survival. RESULTS:From 2009 to 2016, 97 patients were enrolled (68% lumpectomy and 32% mastectomy), among which 92 were treated in the prone position. Five patients were resimulated and treated supine. Among the prone-treated patients, there were no acute toxicities greater than grade 2. A total of 92%, 98%, and 89% met a planning target volume tumor V48 Gy ≥98%, breast V40.5 Gy ≥95%, and nodal V38.5 Gy ≥95%, respectively. All met the heart V5 Gy <5%, contralateral lung V5 Gy <15%, spinal cord dose maximum (Dmax) ≤37.5 Gy, esophagus V30 Gy <50%, and Dmax ≤40.5 Gy. Ninety-eight percent met the ipsilateral lung V10 Gy. Brachial plexus Dmax <42 Gy was met in 74% with a mean increase of 1.61 Gy (SD, 1.96 Gy) over the target. At a median follow-up of 8 years, grade 2 to 3 late toxicity was 23% for prone patients. There were 2 local recurrences (2%) and no chest wall or nodal recurrences. The 8-year distant recurrence-free survival, disease-free survival, and overall survival were 88% (95% CI, 81%-95%), 86% (95% CI, 78%-95%), and 91% (95% CI, 84%-98%), respectively. CONCLUSIONS:Toxicity was low, and outcomes were excellent in this prospective trial of prone hypofractionated nodal RT.

PURPOSE/OBJECTIVE:Our institution was an early adopter of 5-fraction accelerated partial breast irradiation (ABPI) to treat women with early-stage breast cancer. This study reports long-term oncologic and cosmetic outcomes. METHODS:We included patients receiving APBI 600 cGy × 5 fx delivered every other day or every day between 2010 and 2022. Logistic regression models were used to identify factors associated with development of late toxicities, clinician, and patient-rated cosmesis. Kaplan-Meier methodology was used to calculate overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free survival (LR-RFS). RESULTS:442 patients received APBI either daily (56%) or every other day (44%) in the prone position (92%). At a median follow-up of 48 months (range: 5.96-155 months), 12 (2.7%) patients developed a local recurrence (LR). Out of 258 patients with > 3-month toxicity data available, the most common late grade ≥ 2 adverse event was breast fibrosis (6.2%). On multivariate analysis, daily APBI treatment (vs every other day) did not correlate with an increased risk of any late grade ≥ 2 toxicity though it did correlate with a lower risk of any late grade ≥ 2 fibrosis. Overall, at a median follow-up of 80 months, the rates of good-excellent physician and patient-rated cosmesis were 95% and 85%, respectively, with no difference between patients treated on consecutive vs. every other day. On multivariate analysis, patients who did not receive any adjuvant therapy were at increased risk of developing a LR. Five-year OS, LRFS, and DFS were 97.2%, 97.7%, and 89.5%, respectively. CONCLUSIONS:Five-fraction APBI delivered primarily in the prone position either daily or every other day was effective with low rates of local recurrence, minimal toxicity, and excellent cosmesis at long-term follow-up.

PURPOSE/OBJECTIVE:With transition from supine to prone position, tenting of the pectoralis major occurs, displacing the muscle from the chest wall and shifting the level I and II axillary spaces. For patients for whom we aim to treat the level I and II axillae using the prone technique, accurate delineation of these nodal regions is necessary. Although different consensus guidelines exist for delineation of nodal anatomy in supine position, to our knowledge, there are no contouring guidelines in the prone position that account for this change in nodal anatomy. METHODS AND MATERIALS/METHODS:The level I and II nodal contours from the Radiation Therapy Oncology Group (RTOG) breast cancer supine atlas were adapted for prone position by 2 radiation oncologists and a breast radiologist based on anatomic changes observed from supine to prone positioning on preoperative diagnostic imaging. Forty-three patients from a single institution treated with prone high tangents from 2012 to 2018 were identified as representative cases to delineate the revised level I and II axillae on noncontrast computed tomography (CT) scans obtained during radiation simulation. The revised nodal contours were reviewed by an expanded expert multidisciplinary panel including breast radiologists, radiation oncologists, and surgical oncologists for consistency and reproducibility. RESULTS:Consensus was achieved among the panel in order to create modifications from the RTOG breast atlas for CT-based contouring of the level I and II axillae in prone position using bone, muscle, and skin as landmarks. This atlas provides representative examples and accompanying descriptions for the changes described to the caudal and anterior borders of level II and the anterior, posterior, medial, and lateral borders of level I. A step-by-step guide is provided for properly identifying the revised anterior border of the level I axilla. CONCLUSIONS:The adaptations to the RTOG breast cancer atlas for prone positioning will enable radiation oncologists to more accurately target the level I and II axillae when the axillae are targets in addition to the breast.

In this review, we cover the current understanding of how radiation therapy, which uses ionizing radiation to kill cancer cells, mediates an anti-tumor immune response through the cGAS-STING pathway, and how STING agonists might potentiate this. We examine how cGAS-STING signaling mediates the release of inflammatory cytokines in response to nuclear and mitochondrial DNA entering the cytoplasm. The significance of this in the context of cancer is explored, such as in response to cell-damaging therapies and genomic instability. The contribution of the immune and non-immune cells in the tumor microenvironment is considered. This review also discusses the burgeoning understanding of STING signaling that is independent of inflammatory cytokine release and the various mechanisms by which cancer cells can evade STING signaling. We review the available data on how ionizing radiation stimulates cGAS-STING signaling as well as how STING agonists may potentiate the anti-tumor immune response induced by ionizing radiation. There is also discussion of how novel radiation modalities may affect cGAS-STING signaling. We conclude with a discussion of ongoing and planned clinical trials combining radiation therapy with STING agonists, and provide insights to consider when planning future clinical trials combining these treatments.

PURPOSE/OBJECTIVE:This guideline provides evidence-based recommendations on appropriate indications and techniques for partial breast irradiation (PBI) for patients with early-stage invasive breast cancer and ductal carcinoma in situ. METHODS:The American Society for Radiation Oncology (ASTRO) convened a task force to address 4 key questions focused on the appropriate indications and techniques for PBI as an alternative to whole breast irradiation (WBI) to result in similar rates of ipsilateral breast recurrence (IBR) and toxicity outcomes. Also addressed were aspects related to the technical delivery of PBI including dose-fractionation regimens, target volumes, and treatment parameters for different PBI techniques. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS:PBI delivered using 3-D conformal radiation therapy, intensity modulated radiation therapy, multicatheter brachytherapy and single-entry brachytherapy result in similar IBR as WBI with long-term follow-up. Some patient characteristics and tumor features were underrepresented in the randomized controlled trials, making it difficult to fully define IBR risks for patients with these features. Appropriate dose-fractionation regimens, target volume delineation, and treatment planning parameters for delivery of PBI are outlined. Intraoperative radiation therapy alone is associated with a higher IBR rate compared to WBI. A daily or every other day external beam PBI regimen is preferred over twice daily regimens due to late toxicity concerns. CONCLUSIONS:Based on published data, the ASTRO task force has proposed recommendations to inform best clinical practices on the use of PBI.

PURPOSE/OBJECTIVE:Acute radiation dermatitis (ARD) is common after radiation therapy for breast cancer, with data indicating that ARD may disproportionately affect Black or African American (AA) patients. We evaluated the effect of skin of color (SOC) on physician-reported ARD in patients treated with radiation therapy. METHODS AND MATERIALS/METHODS:We identified patients treated with whole breast or chest wall ± regional nodal irradiation or high tangents using 50 Gy in 25 fractions from 2015 to 2018. Baseline skin pigmentation was assessed using the Fitzpatrick scale (I = light/pale white to VI = black/very dark brown) with SOC defined as Fitzpatrick scale IV to VI. We evaluated associations among SOC, physician-reported ARD, late hyperpigmentation, and use of oral and topical treatments for RD using multivariable models. RESULTS:A total of 325 patients met eligibility, of which 40% had SOC (n = 129). On multivariable analysis, Black/AA race and chest wall irradiation had a lower odds of physician-reported grade 2 or 3 ARD (odds ratio [OR], 0.110; 95% confidence interval [CI], 0.030-0.397; P = .001; OR, 0.377; 95% CI, 0.161-0.883; P = .025), whereas skin bolus (OR, 8.029; 95% CI, 3.655-17.635; P = 0) and planning target volume D0.03cc (OR, 1.001; 95% CI, 1.000-1.001; P = .028) were associated with increased odds. On multivariable analysis, SOC (OR, 3.658; 95% CI, 1.236-10.830; P = .019) and skin bolus (OR, 26.786; 95% CI, 4.235-169.432; P = 0) were associated with increased odds of physician-reported late grade 2 or 3 hyperpigmentation. There was less frequent use of topical steroids to treat ARD and more frequent use of oral analgesics in SOC versus non-SOC patients (43% vs 63%, P < .001; 50% vs 38%, P = .05, respectively). CONCLUSIONS:Black/AA patients exhibited lower odds of physician-reported ARD. However, we found higher odds of late hyperpigmentation in SOC patients, independent of self-reported race. These findings suggest that ARD may be underdiagnosed in SOC when using the physician-rated scale despite this late evidence of radiation-induced skin toxicity.