Radiation therapy for triple-negative breast cancer: from molecular insights to clinical perspectives.

INTRODUCTION: Triple-negative breast cancer (TNBC) lacks three common receptors, making traditional treatments less effective. This review highlights the importance of radiotherapy and emerging therapeutic strategies to enhance treatment outcomes in TNBC. AREAS COVERED: We conducted a literature search on PubMed for publications from 2000 to 2023 to discuss the critical role of radiotherapy in managing TNBC, emphasizing its applications from locoregional control to improving survival rates. The review explores molecular mechanisms underlying TNBC's radiotherapy response, including DNA damage repair and apoptosis, with a focus on BRCA1/2 mutations and Poly (ADP-ribose) polymerase (PARP) inhibition. We summarize preclinical and clinical research on radiosensitization strategies, from gene-targeted therapies to immunotherapy combinations, and the impact of post-mastectomy radiation therapy on locoregional control. The potential of personalized treatment approaches, integrating molecular profiling, targeted radiosensitizers, and the synergistic effects of radiotherapy with immunotherapy, is also discussed. EXPERT OPINION: Future TNBC treatment strategies should focus on precision medicine, integrating immunotherapy, developing novel radiosensitizers, and targeting biological pathways to overcome radioresistance. The integration of radiomics and artificial intelligence offers promising avenues for enhancing treatment personalization and efficacy, aiming to improve patient outcomes in TNBC.

Long-Term Clinical and Cosmetic Outcomes of Once-Daily Accelerated Partial Breast Irradiation in Early Breast Cancer.

Purpose: Accelerated partial breast irradiation (APBI) is one of the standard treatment options in early-stage node negative breast cancer in selected patients. However, the optimal dose fractionation schedule still represents a challenge. We present the 12-year follow up results of clinical and cosmetic outcomes of once daily APBI with external beam radiation therapy which provides an APBI radiation dose equivalent to the whole breast radiation with a boost. Methods and Materials: From July 2008 to August 2010, we enrolled 34 patients with T1, T2 (< 3cm) N0 to receive once daily APBI with three dimensional conformal radiation therapy (3D-CRT) to a total dose of 49.95 Gy over 15 single daily fractions over 3 weeks at 3.33 Gy per fraction. Ipsilateral breast tumor recurrence (IBTR), acute toxicity, late toxicity and cosmesis was analyzed. The median follow-up for all patients is 144 months (12 years). Results: The median age of the patients was 61 years (range 46-83). Nine patients had ductal carcinoma in situ (DCIS) and 25 patients had invasive cancer. The median size of the tumor with DCIS pathology was 0.5 cm, while median size of the tumor with invasive cancer pathology was 1.0 cm. All of the patients had negative margins and negative nodes. Two IBTR was observed (5.8%). One patient had DCIS at recurrence and other had invasive recurrence. Two patients died due to non-cancer cause. The 12-year actuarial ipsilateral breast recurrence free survival was 93.5% and the 12-year actuarial overall survival was 93.2%. Late Grade 2 toxicity was observed in 6 patients and late grade 3 toxicity was seen in 1 patient. 91% of the patients had excellent to good cosmesis. Conclusions: This novel APBI dosing schema is based on an equivalent dose compared to whole breast radiation plus a tumor bed boost. This once daily APBI scheme is well-tolerated and demonstrates good to excellent cosmetic outcome and low rates of late complications on long term follow-up.

Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.

PURPOSE: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.

Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer.

BACKGROUND: Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes. METHODS: To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy. RESULTS: Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically 'cold' tumors to 'hot', via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry. CONCLUSIONS: Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.

Clinical efficacy of PARP inhibitors in breast cancer.

BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.

Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Interstitial Brachytherapy Is Safe: First Results From the Tri-fraction Radiation Therapy Used to Minimize Patient Hospital Trips (TRIUMPH-T) Trial.

PURPOSE: Shorter courses of breast radiotherapy are offered as an alternative to 4 weeks of whole-breast irradiation after lumpectomy, including brachytherapy. A prospective phase 2multi-institution clinical trial to study 3-fraction accelerated partial breast irradiation delivered by brachytherapy was conducted. METHODS AND MATERIALS: The trial treated selected breast cancers after breast-conserving surgery with brachytherapy applicators that delivered 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 2 cm beyond the surgical cavity. Eligible women were age ≥45 years with unicentric invasive or in situ tumors ≤3 cm excised with negative margins and with positive estrogen or progesterone receptors and no metastases to axillary nodes. Strict dosimetric parameters were required to be met and follow up information was collected from the participating sites. RESULTS: Two hundred patients were prospectively enrolled; however, a total of 185 patients who were enrolled were followed for a median of 3.63 years. Three-fraction brachytherapy was associated with low chronic toxicity. There was excellent or good cosmesis in 94% of patients. There were no grade 4 toxicities. Grade 3 fibrosis at the treatment site was present in 1.7% and 32% percent had grades 1 or 2 fibrosis at the treatment site. There was 1 rib fracture. Other late toxicities included 7.4% grade 1 hyperpigmentation, 2% grade 1 telangiectasias, 1.7% symptomatic seromas, 1.7% abscessed cavities, and 1.1% symptomatic fat necrosis. There were 2 (1.1%) ipsilateral local recurrences, 2 (1.1%) nodal recurrences and no distant recurrences. Other incidents included one contralateral breast cancer and 2 second malignancies (lung). CONCLUSIONS: Ultra-short breast brachytherapy is feasible and has excellent toxicity and could be an alternative to standard 5-day, 10 fraction accelerated partial breast irradiation in eligible patients. Patients from this prospective trial will continue to be followed to evaluate long-term outcomes.

Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance).

PURPOSE: Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS: Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS: Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION: The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

The American Society for Radiation Oncology Workforce Taskforce Review of the United States Radiation Oncology Workforce Analysis.

Over the past decade, concerns have arisen in radiation oncology regarding potential workforce supply and demand imbalance. The American Society for Radiation Oncology commissioned an independent analysis in 2022, looking at supply and demand in the United States radiation oncology workforce and projecting future trends for 2025 and 2030. The final report, titled Projected Supply and Demand for Radiation Oncologists in the U.S. in 2025 and 2030, is now available. The analysis included evaluating radiation oncologist (RO) supply (new graduates, exits from the specialty), potential changes in demand (growth of Medicare beneficiaries, hypofractionation, loss of indications, new indications) as well as RO productivity (growth of work relative value units [wRVUs] produced), and demand per beneficiary. The results demonstrated a relative balance between radiation oncology supply and demand for radiation services; the growth in ROs was balanced by the rapid growth of Medicare beneficiaries over the same period. The primary factors driving the model were found to be growth of Medicare beneficiaries and change in wRVU productivity, with hypofractionation and loss of indication having only a moderate effect; although the most likely scenario was a balance of workforce supply and demand, scenarios did demonstrate the possibility of over- and undersupply. Oversupply may become a concern if RO wRVU productivity reaches the highest region; beyond 2030, this is also possible if growth in RO supply does not parallel Medicare beneficiary growth, which is projected to decline and will require corresponding supply adjustment. Limitations of the analysis included uncertainty regarding the true number of ROs, the lack of inclusion of most technical reimbursement and its effect as well as failing to account for stereotactic body radiation therapy. A modeling tool is available to allow individuals to evaluate different scenarios. Moving forward, continued study will be needed to evaluate trends (particularly wRVU productivity and Medicare beneficiary growth) to allow for continued assessment of workforce supply and demand in radiation oncology.

Reconstructive complications and early toxicity in breast cancer patients treated with proton-based postmastectomy radiation therapy.

Background: Postmastectomy radiation therapy (PMRT) decreases the risk of locoregional recurrence and increases overall survival rates in patients with high-risk node positive breast cancer. While the number of breast cancer patients treated with proton-based PMRT has increased in recent years, there is limited data on the use of proton therapy in the postmastectomy with reconstruction setting. In this study, we compared acute toxicities and reconstructive complications in patients treated with proton-based and photon-based PMRT. Methods: A retrospective review of our institutional database was performed to identify breast cancer patients treated with mastectomy with implant or autologous reconstruction followed by PMRT from 2015 to 2020. Baseline clinical, disease, and treatment related factors were compared between the photon-based and proton-based PMRT groups. Early toxicity outcomes and reconstructive complications following PMRT were graded by the treating physician. Results: A total of 11 patients treated with proton-based PMRT and 26 patients treated with photon-based PMRT were included with a median follow-up of 7.4 months (range, 0.7-33 months). Six patients (55%) in the proton group had a history of breast cancer (3 ipsilateral and 3 contralateral) and received previous RT 38 months ago (median, range 7-85). There was no significant difference in mean PMRT (p = 0.064) and boost dose (p = 0.608) between the two groups. Grade 2 skin toxicity was the most common acute toxicity in both groups (55% and 73% in the proton and photon group, respectively) (p = 0.077). Three patients (27%) in the proton group developed grade 3 skin toxicity. No Grade 4 acute toxicity was reported in either group. Reconstructive complications occurred in 4 patients (36%) in the proton group and 8 patients (31%) in photon group (p = 0.946). Conclusions: Acute skin toxicity remains the most frequent adverse event in both proton- and photon-based PMRT. In our study, reconstructive complications were not significantly higher in patients treated with proton- versus photon-based PMRT. Longer follow-up is warranted to assess late toxicities.

The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer.

The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.

Early Toxicity and Patient-Reported Cosmetic Outcomes in Patients Treated With Adjuvant Proton-Based Radiotherapy After Breast-Conserving Surgery.

INTRODUCTION: To evaluate the dosimetric data, early toxicity, and patient-reported cosmetic outcomes in breast cancer patients treated with adjuvant proton-based radiotherapy (RT) after breast-conserving surgery. MATERIALS AND METHODS: We performed a retrospective review of our institutional database to identify breast cancer patients treated with breast-conserving surgery followed by proton-based RT from 2015 to 2020. Patient-reported cosmetic outcomes were graded as excellent, good, fair, or poor. Early toxicity outcomes were graded by the treating physician during treatment. Dose-volume histograms were reviewed to obtain dosimetry data. RESULTS: We identified 21 patients treated with adjuvant proton-based RT. Median whole breast dose delivered was 46.8 Gy (range, 40.0-50.4 Gy). Target volumes included the regional lymph nodes in 17 patients (81%). Seventeen patients (81%) received a lumpectomy boost. The median planning target volume V95 was 94% (range, 77%-100%), V100 71% (range, 60%-97%), V110 2% (range 0%-18%), and median max point dose was 115% (range, 105%-120%). The median ipsilateral breast V105 was 367.3 cc (range, 0-1172 cc) and V110 was 24.1 cc (range, 0-321.3 cc). Grade 2 and 3 dermatitis occurred in 62% and 14% of patients, respectively. Grade 2 and 3 pain was reported by 33% and 10% of patients, respectively. Median follow-up at the time of cosmetic evaluation was 27 months (range, 5-42 months). Four patients (21%) reported fair cosmetic outcome and 15 patients (79%) reported good or excellent cosmetic outcome. No poor cosmesis was reported. CONCLUSION: Adjuvant proton-based radiotherapy after breast-conserving surgery is well tolerated with acceptable rates of acute toxicities and a high rate of good-to-excellent patient-reported cosmetic outcomes.

Consensus Quality Measures and Dose Constraints for Breast Cancer From the Veterans Affairs Radiation Oncology Quality Surveillance Program and American Society for Radiation Oncology Expert Panel.

PURPOSE: Using evidence-based radiation therapy to direct care for patients with breast cancer is critical to standardize practice, improve safety, and optimize outcomes. To address this need, the Veterans Affairs (VA) National Radiation Oncology Program (NROP) established the VA Radiation Oncology Quality Surveillance Program to develop clinical quality measures (QMs). The VA NROP contracted with the American Society for Radiation Oncology to commission 5 Blue Ribbon Panels for breast, lung, prostate, rectal, and head and neck cancers. METHODS AND MATERIALS: The Breast Cancer Blue Ribbon Panel experts worked collaboratively with the NROP to develop consensus QMs for use throughout the VA system, establishing a set of QMs for patients in several areas, including consultation and work-up; simulation, treatment planning, and treatment; and follow-up care. As part of this initiative, consensus dose-volume histogram (DVH) constraints were outlined. RESULTS: In total, 36 QMs were established. Herein, we review the process used to develop QMs and final consensus QMs pertaining to all aspects of radiation patient care, as well as DVH constraints. CONCLUSIONS: The QMs and expert consensus DVH constraints are intended for ongoing quality surveillance within the VA system and centers providing community care for Veterans. They are also available for use by greater non-VA community measures of quality care for patients with breast cancer receiving radiation.

Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer.

The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.