Guideline-Concordant Surgical Care for Lobular Versus Ductal Inflammatory Breast Cancer.

INTRODUCTION: Quality of surgical care is understudied for lobular inflammatory breast cancer (IBC), which is less common, more chemotherapy-resistant, and more mammographically occult than ductal IBC. We compared guideline-concordant surgery (modified radical mastectomy [MRM] without immediate reconstruction following chemotherapy) for lobular versus ductal IBC. METHODS:  Female individuals with cT4dM0 lobular and ductal IBC were identified in the National Cancer Database (NCDB) from 2010-2019. Modified radical mastectomy receipt was identified via codes for "modified radical mastectomy" or "mastectomy" and "≥10 lymph nodes removed" (proxy for axillary lymph node dissection). Descriptive statistics, chi-square tests, and t-tests were used. RESULTS: A total of 1456 lobular and 10,445 ductal IBC patients were identified; 599 (41.1%) with lobular and 4859 (46.5%) with ductal IBC underwent MRMs (p = 0.001). Patients with lobular IBC included a higher proportion of individuals with cN0 disease (20.5% lobular vs. 13.7% ductal) and no lymph nodes examined at surgery (31.2% vs. 24.5%) but were less likely to be node-negative at surgery (12.7% vs. 17.1%, all p < 0.001). Among those who had lymph nodes removed at surgery, patients with lobular IBC also had fewer lymph nodes excised versus patients with ductal IBC (median [interquartile range], 7 (0-15) vs. 9 (0-17), p = 0.001). CONCLUSIONS: Lobular IBC patients were more likely to present with node-negative disease and less likely to be node-negative at surgery, despite having fewer, and more frequently no, lymph nodes examined versus ductal IBC patients. Future studies should investigate whether these treatment disparities are because of surgical approach, pathologic assessment, and/or data quality as captured in the NCDB.

Association of Moderate-Risk Breast Cancer Genes with Contralateral Prophylactic Mastectomy and Bilateral Disease.

BACKGROUND: The impact of ATM, CHEK2, and PALB2, the three most prevalent moderate-risk breast cancer genes, on surgical decision making is not well known. METHODS: Our retrospective study included patients with resectable non-metastatic breast cancer who underwent multigene panel testing between July 2014 and January 2020 with at least one genetic alteration (pathogenic or variant of uncertain significance [VUS] in ATM [n = 49], CHEK [n = 57], or PALB2 [n = 27]). Our objectives were to determine the rate of contralateral prophylactic mastectomy (CPM) and the rate of bilateral breast cancer. Univariable analyses (UVA) and multivariable analyses (MVA) were performed to identify factors associated with CPM and bilateral breast cancer. RESULTS: The rate of CPM was 39% (n = 49/127), with 54% (n = 25/46) of patients with a pathogenic mutation and 30% (n = 24/81) of patients with a VUS choosing CPM. On MVA, premenopausal status (odds ratio [OR] 3.46) and a pathogenic alteration (OR 3.01) were associated with increased use of CPM. Bilateral disease was noted in 16% (n = 22/138). Patients with pathogenic mutations had a 22% (n = 11/51) incidence of bilateral breast cancer, while patients with VUS had a 13% (n = 11/87) incidence, although this was not statistically significant on UVA or MVA. On MVA, premenopausal status was associated with a decreased risk of bilateral disease (OR 0.33, p = 0.022). During follow-up, a breast cancer event occurred in 16% (n = 22/138). CONCLUSIONS: Our study identified a high rate of CPM among those with ATM, CHEK2, and PALB2 alterations, including VUS. Further studies are needed to clarify reasons for CPM among patients with moderate-risk alterations.

Temporal Trends and Factors Associated with Receipt of Post-mastectomy Radiation After Neoadjuvant Chemotherapy in Women with cT3 Breast Cancer.

INTRODUCTION: Given the potential impact of increasingly effective neoadjuvant chemotherapy (NACT) on post-mastectomy radiotherapy (PMRT) recommendations, we examined temporal trends in post-NACT PMRT for cT3 breast cancer. METHODS: We identified women ≥ 18 years in the National Cancer Database (NCDB) diagnosed 2004-2019 with cT3N0-1M0 breast cancer treated with chemotherapy and mastectomy. Multivariable logistic regression and Cox proportional hazards models were used to estimate associations between pathologic NACT response [complete response (CR), partial response (PR), or no response (NR); or disease progression (DP)] and PMRT and between PMRT and overall survival (OS), respectively. RESULTS: We identified 39,901 women (Asian/Pacific Islander 1731, Black 5875, Hispanic 3265, White 27,303). Among cN0 patients with CR, PMRT rates declined from 67% in 2004 to 35% in 2019 but remained unchanged for patients with DP. Relative to NR, CR [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.29-0.46] and PR (OR 0.44, 95% CI 0.36-0.55) in cN0 patients were associated with lower odds of PMRT while DP (OR 1.33, 95% CI 1.05-1.69) was associated with higher odds. Among cN1 patients, PMRT rates decreased from 90% to 73% for CR between 2005 and 2019 and increased from 76% to 82% for DP between 2004 and 2019. Relative to NR, CR (OR 0.78, 95% CI 0.63-0.95) was associated with lower odds of PMRT while DP (OR 1.93, 95% CI 1.58-2.37) was associated with higher odds. PMRT was associated with improved OS among cN1 patients (hazard ratio (HR) 0.77, 95% CI 0.67-0.88). CONCLUSION: CR was associated with decreased PMRT receipt over time, while temporal trends following PR and DP differed by cN status, suggesting that nodal involvement guided PMRT receipt more than in-breast disease.

Up-Regulation of DNA Damage Response Signaling in Autosomal Dominant Polycystic Kidney Disease.

DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.6-fold compared with that in normal kidney, and by 2.5-fold in cystic compared with that in minimally cystic tissue (P < 0.0001). In end-stage human ADPKD tissue, γ-H2A histone family member X (H2AX), phosphorylated ataxia telangiectasia and radiation-sensitive mutant 3 (Rad3)-related (pATR), and phosphorylated ataxia telangiectasia mutated (pATM) localized to cystic kidney epithelial cells. In vitro, pATR and pATM were also constitutively increased in human ADPKD tubular cells (WT 9-7 and 9-12) compared with control (HK-2). In addition, extrinsic oxidative DNA damage by hydrogen peroxide augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the three-dimensional Madin-Darby canine kidney cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1RC/RC mice, and not altered at later time points up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.

Longitudinal Prospective Evaluation of Quality of Life After Axillary Lymph Node Dissection.

BACKGROUND: Patients often fear axillary lymph node dissection (ALND) because of its associated complications; however, its effect on quality of life (QOL) is not well described. We aimed to evaluate the effect of ALND on QOL over time and to identify predictors of worse QOL. PATIENTS AND METHODS: Breast cancer patients undergoing ALND were enrolled in a prospective lymphedema screening study. Arm volumes were measured and QOL questionnaires completed at baseline, postoperatively, and at 6-month intervals. The upper limb lymphedema-27 questionnaire was used to assess the effect of upper extremity symptoms on QOL in three domains (physical, psychological, and social). Predictors of QOL were identified by univariate and multivariable regression analyses. RESULTS: From November 2016 through March 2020, 304 ALND patients were enrolled; 242 patients with at least two measurements and 6 months of follow-up were included. Median age was 48 years, and median follow-up was 1.2 years. The 18-month lymphedema rate was 18%. Overall, QOL scores in all three domains decreased postoperatively and improved over time. On multivariable analysis, after adjusting for baseline scores, symptoms necessitating lymphedema therapy referral (p = 0.006) were associated with worse physical QOL. Younger age (p = 0.005) and lymphedema therapy referral (p = 0.006) were associated with worse psychological QOL. Arm volume was not correlated with QOL. CONCLUSIONS: QOL scores initially decreased after ALND but improved by 6 months post-surgery. Decreases in QOL were independent of arm volume. Patients with worse QOL more often sought lymphedema therapy, although the effect of therapy on QOL remains unknown.

Burnout and Professional Fulfillment in Early and Early-Mid-Career Breast Surgeons.

BACKGROUND: Prior work has shown that burnout among breast surgeons is prevalent and highest in those earlier in their clinical practice career. Therefore, we sought to better understand and identify specific contributors to early-career breast surgeon burnout. METHODS: We analyzed data from our 2017 survey of members of the American Society of Breast Surgeons. The 16-items of the Professional Fulfillment Index were used in determining overall burnout and professional fulfillment scores. Multivariable regressions were performed to evaluate factors related to overall burnout and professional fulfillment. RESULTS: The mean overall burnout score was 1.23 (0-4 scale; higher score unfavorable) for surgeons in practice < 5 years, compared with 1.39 for surgeons in practice 5-9 years and 1.22 for those in practice ≥ 10 years. The mean professional fulfillment score was 2.71 (0-4 scale; higher score favorable) for surgeons in practice < 5 years, 2.66 for surgeons in practice 5-9 years, and 2.67 for surgeons in practice ≥ 10 years. Multivariable analysis showed that burnout was positively correlated with ≥ 60 work hours per week in the group practicing for < 5 years, and dedicating less than full time to breast surgery in the group in practice 5-9 years. Professional fulfillment was negatively associated with single relationship status in surgeons practicing < 5 years, and dedicating less than full time to breast surgery for those in practice 5-9 years. CONCLUSION: Our study suggests that breast surgeons who have been in practice for 5-9 years have particularly high overall burnout rates and additional support focused on this group of breast surgeons may be needed.

Immunotherapeutic strategies in breast cancer: A clinical update.

Immunotherapy has been incorporated into the standard of care for a wide range of malignancies. The study of tumor-infiltrating lymphocytes has emphasized the importance of the host antitumor immune response in the natural history of breast cancer. Recent clinical trials have used immunotherapeutic approaches to augment this response and improve outcomes for patients with breast cancer. Here, we review several current clinical trial data that indicate checkpoint blockade may mediate clinically significant responses.

Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in KitV558Δ;Y719F/Y719F mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing KitV558Δ/+ mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant KitV558Δ;T669I/+ tumors.

The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1-2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.

Assessing Burnout and Professional Fulfillment in Breast Surgery: Results From a National Survey of the American Society of Breast Surgeons.

BACKGROUND: Physician burnout is a well-recognized problem in health care that has a negative impact on professional well-being and quality of patient care. Rates of burnout in breast surgery are not well-defined. This study sought to understand the degree of burnout among breast surgeons and to identify factors that influence professional fulfillment. METHODS: All U.S. members of the American Society of Breast Surgeons with a valid email address were surveyed in October 2017. The results were anonymous, and the participants were blinded to the study hypothesis. The survey included 30 questions (16-item Professional Fulfillment Index [PFI] and 14-item demographics/practice patterns). Multivariable linear regressions were performed to assess overall burnout and high professional fulfillment. RESULTS: Of the 2568 surveys delivered, 708 surveys were initiated, and 660 were completed. Among breast surgeons, 270 (41.3%) expressed burnout, whereas 281 (42.5%) reported high professional fulfillment. In the multivariable analysis, years in practice was inversely associated with burnout and positively correlated with professional fulfillment. Working more than 60 h per week was positively associated with burnout, and having more than 50% of practice dedicated to breast surgery correlated positively with fulfillment. CONCLUSION: Approximately 4 of 10 breast surgeons have symptoms of burnout, whereas 4 of 10 surgeons report high professional fulfillment. Specific clinical practice conditions largely influence rates of burnout and professional fulfillment. The contributing factors identified in the study analysis may be useful in identifying breast surgeons at higher risk for burnout. The study findings also help to inform the design of interventions focused on the clinical practice environment to promote professional fulfillment and sustainability.

Risk factors and indications for readmission after lower extremity amputation in the American College of Surgeons National Surgical Quality Improvement Program.

BACKGROUND: Postoperative readmission, recently identified as a marker of hospital quality in the Affordable Care Act, is associated with increased morbidity, mortality, and health care costs, yet data on readmission after lower extremity amputation (LEA) are limited. We evaluated risk factors for readmission and postdischarge adverse events after LEA in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP). METHODS: All patients undergoing transmetatarsal (TMA), below-knee (BKA), or above-knee amputation (AKA) in the 2011-2012 NSQIP were identified. Independent predischarge predictors of 30-day readmission were determined by multivariable logistic regression. Readmission indication and reinterventions, available in the 2012 NSQIP only, were also evaluated. RESULTS: We identified 5732 patients undergoing amputation (TMA, 12%; BKA, 51%; AKA, 37%). Readmission rate was 18%. Postdischarge mortality rate was 5% (TMA, 2%; BKA, 3%; AKA, 8%; P < .001). Overall complication rate was 43% (in-hospital, 32%; postdischarge, 11%). Reoperation was for wound-related complication or additional amputation in 79% of cases. Independent predictors of readmission included chronic nursing home residence (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.7), nonelective surgery (OR, 1.4; 95% CI, 1.1-1.7), prior revascularization/amputation (OR, 1.4; 95% CI, 1.1-1.7), preoperative congestive heart failure (OR, 1.7; 95% CI, 1.2-2.4), and preoperative dialysis (OR, 1.5; 95% CI, 1.2-1.9). Guillotine amputation (OR, 0.6; 95% CI, 0.4-0.9) and non-home discharge (OR, 0.7; 95% CI, 0.6-1.0) were protective of readmission. Wound-related complications accounted for 49% of readmissions. CONCLUSIONS: Postdischarge morbidity, mortality, and readmission are common after LEA. Closer follow-up of high-risk patients, optimization of medical comorbidities, and aggressive management of wound infection may play a role in decreasing readmission and postdischarge adverse events.

Risk factors for readmission after lower extremity bypass in the American College of Surgeons National Surgery Quality Improvement Program.

OBJECTIVE: Readmission is associated with high mortality, morbidity, and cost. We used the American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP) to determine risk factors for readmission after lower extremity bypass (LEB). METHODS: We identified all patients who received LEB in the 2011 ACS-NSQIP database. Multivariable logistic regression was used to assess independent predictors of 30-day readmission. We also identified our institutional contribution of LEB patients to the ACS-NSQIP from 2005 to 2011 to determine our institution's rate of readmission and readmission indications. RESULTS: Among 5018 patients undergoing LEB, ACS-NSQIP readmission analysis was performed on 4512, excluding those whose readmission data were unavailable, who suffered a death on index admission, or who remained in the hospital at 30 days. Overall readmission rate was 18%, and readmission rate of those with NSQIP-captured complications was 8%. Multivariable predictors of readmission were dependent functional status (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.08-1.79), dyspnea (OR, 1.28; 95% CI, 1.02-1.60), cardiac comorbidity (OR, 1.46; 95% CI, 1.16-1.84), dialysis dependence (OR, 1.44; 95% CI, 1.05-1.97), obesity (OR, 1.28; 95% CI, 1.07-1.53), malnutrition (OR, 1.42; 95% CI, 1.12-1.79), critical limb ischemia operative indication (OR, 1.40; 95% CI, 1.10-1.79), and return to the operating room on index admission (OR, 8.0; 95% CI, 6.68-9.60). The most common postdischarge complications occurring in readmitted patients included wound complications (55%), multiple complications (22%), and graft failure (5%). Our institutional data contributed 465 LEB patients to the ACS-NSQIP from 2005 to 2012, with an overall readmission rate of 14%. Unplanned readmissions related to the original LEB (related unplanned) made up 75% of cases. The remainder 25% included readmissions that were planned staged procedures related to the original LEB (related planned, 11%) and admissions for a completely unrelated reason (unrelated unplanned, 14%). The most common readmission indications included wound infection (37%) and graft failure (10%). Readmissions were attributable to NSQIP-captured postdischarge complications in 44% of cases, an additional 44% had a non-NSQIP-defined reason for readmission, and the remainder (12%) included patients admitted for complications described in NSQIP but not meeting strict NSQIP criteria. CONCLUSIONS: Readmissions are common after LEB. Optimization of select chronic conditions, closer follow-up of patients in poor health and those who required return to the operating room, and early detection of surgical site infections may improve readmission rates. Our finding that 25% of readmissions after LEB are not procedure related informs the broader discussion of how a readmission penalty affects vascular surgery in particular.

Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor.

PURPOSE: To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. EXPERIMENTAL DESIGN: We created a patient-derived xenograft (PDX) of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light-chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression. RESULTS: The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the antitumor effects of low-dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. CONCLUSIONS: MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.

Prescribed Water Intake in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Arginine vasopressin promotes kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Increased water intake reduces arginine vasopressin and urine osmolality and may slow kidney cyst growth. METHODS: In this randomized controlled 3-year clinical trial, we randomly assigned adults with ADPKD who had a height-corrected total kidney volume in Mayo imaging subclass categories 1B to 1E and an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or greater to (1) water intake prescribed to reduce 24-hour urine osmolality to 270 mOsmol/kg or less or (2) ad libitum water intake irrespective of 24-hour urine osmolality. The primary end point was the percentage annualized rate of change in height-corrected total kidney volume. RESULTS: A total of 184 patients participated in either the ad libitum water intake group (n=92) or the prescribed water intake group (n=92). Over 3 years, there was no difference in the annualized rate of change in height-corrected total kidney volume between the ad libitum (7.8% per year; 95% confidence interval [CI], 6.6 to 9.0) and prescribed (6.8% per year; 95% CI, 5.8 to 7.7) water intake groups (mean difference, −0.97% per year; 95% CI, −2.37 to 0.44; P=0.18). The difference in mean 24-hour urine osmolality between the ad libitum and prescribed water intake groups was −91 mOsmol/kg (95% CI, −127 to −54 mOsmol/kg), with 52.3% of patients achieving adherence to the target 24-hour urine osmolality and no reduction in serum copeptin over 3 years. The frequency of adverse events was similar between groups. CONCLUSIONS: For patients with ADPKD, prescribed water intake was not associated with excess adverse events and achieved the target 24-hour urine osmolality for half of the patients but did not reduce copeptin or slow the growth of total kidney volume over 3 years compared with ad libitum water intake. (Funded by the National Health and Medical Research Council of Australia [grant GNT1138533], Danone Research, PKD Australia, the University of Sydney, and the Westmead Medical Research Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12614001216606).

Differential response of the plant Medicago truncatula to its symbiont Sinorhizobium meliloti or an exopolysaccharide-deficient mutant.

Sinorhizobium meliloti forms symbiotic, nitrogen-fixing nodules on the roots of Medicago truncatula. The bacteria invade and colonize the roots through structures called infection threads. S. meliloti unable to produce the exopolysaccharide succinoglycan are unable to establish a symbiosis because they are defective in initiating the production of infection threads and in invading the plant. Here, we use microarrays representing 16,000 M. truncatula genes to compare the differential transcriptional responses of this host plant to wild-type and succinoglycan-deficient S. meliloti at the early time point of 3 days postinoculation. This report describes an early divergence in global plant gene expression responses caused by a rhizobial defect in succinoglycan production, rather than in Nod factor production. The microarray data show that M. truncatula inoculated with wild-type, succinoglycan-producing S. meliloti more strongly express genes encoding translation components, protein degradation machinery, and some nodulins than plants inoculated with succinoglycan-deficient bacteria. This finding is consistent with wild-type-inoculated plants having received a signal, distinct from the well characterized Nod factor, to alter their metabolic activity and prepare for invasion. In contrast, M. truncatula inoculated with succinoglycan-deficient S. meliloti more strongly express an unexpectedly large number of genes in two categories: plant defense responses and unknown functions. One model consistent with our results is that appropriate symbiotically active exopolysaccharides act as signals to plant hosts to initiate infection thread formation and that, in the absence of this signal, plants terminate the infection process, perhaps via a defense response.

Effect of Reducing Ataxia-Telangiectasia Mutated (ATM) in Experimental Autosomal Dominant Polycystic Kidney Disease.

The DNA damage response (DDR) pathway is upregulated in autosomal dominant polycystic kidney disease (ADPKD) but its functional role is not known. The ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) protein kinases are key proximal transducers of the DDR. This study hypothesized that reducing either ATM or ATR attenuates kidney cyst formation and growth in experimental ADPKD. In vitro, pharmacological ATM inhibition by AZD0156 reduced three-dimensional cyst growth in MDCK and human ADPKD cells by up to 4.4- and 4.1-fold, respectively. In contrast, the ATR inhibitor, VE-821, reduced in vitro MDCK cyst growth but caused dysplastic changes. In vivo, treatment with AZD0156 by oral gavage for 10 days reduced renal cell proliferation and increased p53 expression in Pkd1RC/RC mice (a murine genetic ortholog of ADPKD). However, the progression of cystic kidney disease in Pkd1RC/RC mice was not altered by genetic ablation of ATM from birth, in either heterozygous (Pkd1RC/RC/Atm+/-) or homozygous (Pkd1RC/RC/Atm-/-) mutant mice at 3 months. In conclusion, despite short-term effects on reducing renal cell proliferation, chronic progression was not altered by reducing ATM in vivo, suggesting that this DDR kinase is dispensable for kidney cyst formation in ADPKD.