Radiation recall dermatitis (RRD) is an uncommon dermatologic reaction provoked notably by chemotherapy in an area of skin irradiated weeks to years prior. We report a case of RRD with nivolumab in a woman with breast cancer. The patient was diagnosed with invasive ductal carcinoma of the left breast with an isolated spinal metastasis approached in an oligometastatic fashion with neoadjuvant chemotherapy, modified radical mastectomy and adjuvant radiotherapy. Unfortunately, after progression of bony metastases treated with radiotherapy, the patient received nivolumab and subsequently developed a rash corresponding to the adjuvant radiation field. This case highlights the unpredictable nature and characteristic rash of RRD. It is an important differential diagnosis for multidisciplinary teams who also see chemotherapy-induced dermatitis and immune-related adverse events.
Materials/Methods: To test if ESR1 mutations influence response to radiation therapy, we employed ER-positive MCF7 and T47D cell lines which have been genome edited to knock in two of the most common ESR1 mutations found in breast cancer patients (Y537S and D538G). Clonogenic survival assays were carried out to characterize differences in radiation sensitivity of these cells. g-H2AX and Comet assays were employed to study the differences in residual unrepaired DNA damage following radiation in these cell lines. MCF7 cell linederived xenografts harboring the wild type or mutant ESR1 were employed to study differences in radiation resistance of these tumors in vivo. Results: ER-positive breast cancer cell lines harboring ESR1 mutations exhibit resistance to radiation compared to the corresponding isogenic cell lines with the wild type ESR1. Following exposure to radiation, the ESR1 mutant cells have significantly less residual, unrepaired DNA damage. We also show an endogenous interaction between mutant ER proteins and BRD4, a bromodomain and extraterminal domain (BET) family protein. Recent studies have established a key role for BRD4 in repairing DNA double strand breaks via non-homologous end joining pathway. Pharmacologic BET inhibition with OTX015 overcomes ESR1 mutation-induced resistance to therapeutic radiation in breast cancer, both in vitro and in vivo. Conclusion: ESR1 mutations, which confer resistance to endocrine therapies, also confer resistance to radiation therapy. Recent studies show that ESR1 mutations are also enriched in non-metastatic, ER-positive breast cancer patients receiving neoadjuvant endocrine therapy. Our findings suggest that patients who develop ESR1 mutations under selective pressure of neoadjuvant endocrine therapy may respond poorly to subsequent radiation therapy and may experience increased risk of locoregional failure. In fact, a recent study reported enrichment of ESR1 mutations in locoregionally recurrent breast cancers. Our findings support prospective clinical studies for personalization of radiation treatments in breast cancer based on ESR1 mutation status.
scanning proton system using conventional, FLASH, and pulsed-FLASH (0.5 Gy/sec, 40 Gy/sec, 40 Gy/sec at 10% duty cycle respectively), then sacrificed at 8, 16, 24 and 36 week timepoints. Over the course of animal husbandry, the animals were monitored for weight, radiation induced dermatitis, and lung function using barometric plethysmography. A timeto-event analysis quantified the degree of skin damage and breathing function. Upon sacrifice, the harvested lung tissues were either paraffin embedded or frozen. The paraffin embedded samples were stained with H&E and Masson's Trichrome then evaluated by a board-certified pathologist and by internally developed algorithms to quantify the degree of lung fibrosis. Frozen tissues were sectioned and stained for various modes of cell death and then digitally quantified. Results: Overall, the differences between the treatment types occurred in the higher dose groups, namely 17.5, 20 Gy, with very little difference observed at 15 Gy. Gender differences were also observed for most of the endpoints, namely male mice did not respond differently to dose-rate, whereas female mice in the FLASH group showed better overall survival, lower incidence of dermatitis, better breathing function, and differences in lung pathology. Differences in mode of cell death were also observed between FLASH/pulsed-FLASH and Conventional groups with no apparent gender differences. Conclusion: This study is the first to report the effects of FLASH irradiation using pencil beam proton irradiation. The results of this toxicity study help to corroborate the emerging evidence that ultra-high dose rates help spare healthy tissue from radiation induced toxicity on a platform capable of translation to human trials.
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