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Abstract Background: About 10-20% of breast cancers (BC) are hereditary. Patients (pts) with BC and pathogenic variants (PVs) in the BRCA1 or BRCA2 gene are at increased risk of contralateral breast cancer (CBC). However, risks of CBC and recurrent BC associated with PVs in other established BC predisposition genes (e.g. PALB2, CHEK2, ATM) are less well established. We performed research genetic testing of over 4000 pts with BC treated at Mayo Clinic. Because most pts were unaware of their mutation status prior to selection of therapy, this cohort provides a unique opportunity to evaluate the natural history of BC recurrence after treatment of the index BC in pts with a deleterious mutation in predisposition genes. Methods: Women diagnosed and treated for BC at Mayo Clinic between 2001-2016 were enrolled in an IRB-approved research cohort. Pts were not selected for age of diagnosis or family history. Coding regions and consensus splice sites of established BC predisposition genes were subjected to amplicon-based deep sequencing using the QIAseq method in germline DNA extracted from peripheral blood or buccal samples. PVs in the genes were identified using GATK haplotype caller and Vardict. Patient, tumor, oncologic management and follow up data were reviewed. Herein we report on the differences in the incidence of local recurrence and CBC, among carriers and non- carriers and by predisposition gene using the cumulative incidence estimator and Fine and Gray regression to account for competing risks. Results: Of 4272 women with BC (median age 57, range 21-94), a PV in a BC predisposition gene was identified in 287 (6.7%). The most common PVs were seen in CHEK2 (67, 1.6%), BRCA1 (62, 1.5%), BRCA2 (60, 1.4%), ATM (47, 1.1%); 8 (0.2%) patients had more than one PV. Pts with any PVs presented at younger age (median 51 vs 58 years, p<0.001), were more likely to have stage IV disease (4.5% vs 2.3%, p=0.02), estrogen receptor (ER) negative BC (19.5% vs 13.5%, p=0.005), and bilateral cancer (8.8% vs 4.3%, p<0.001). ER- BC proportion varied by gene - 38.9% in pts with PVs associated with ER- BC (BRCA1, BARD1, BRIP1, RAD51C, RAD51D) and 11.9% in those with PVs associated with ER+ BC (BRCA2, ATM, CDH1, CHEK2), p<0.001. NCCN criteria for genetic testing were assessed for 3763, with 69.9% of those with PVs qualifying for testing compared to 46.3% of those without PVs (p<0.001). Among 3973 pts (249 with PVs, 3724 without) with unilateral stage 0-III cancer, 168 pts developed local recurrence, 131 pts developed CBC and 248 pts developed distant disease with median 5 years of follow-up. Patients with any PV had higher rates of local recurrence after breast conserving surgery (HR 2.3, 95% CI: 1.2-4.2, p=0.01) but overall did not have significantly higher risk of CBC if contralateral prophylactic mastectomy was not performed (HR 1.7, 95% CI: 0.9-3.2, p=0.11). Specifically, pts with PVs in genes other than BRCA1 or BRCA2 did not have a higher risk of CBC compared to pts with no PV (HR 1.0, 95% CI: 0.4-2.7, p=0.96); the comparison of CBC risk in BRCA1 or BRCA2 versus those with no PV was HR 2.9 (95% CI: 1.3-6.5, p=0.01), while BRCA1 or BRCA2 compared to those with other PVs was HR 2.7 (95% CI: 0.8-9.3, p=0.13). In pts with CHEK2 PVs, the probability of CBC at 10-years follow-up was 5.4%, which was similar to pts without a mutation (5.3%), p=0.47. Conclusion: While PVs in known BC predisposition genes increase risk of BC development, risk of CBC in carriers of PVs in non-BRCA predisposition genes with BC are not as high as seen with BRCA1 or 2 PV carriers. This information regarding future BC will be helpful in personalizing decisions on the extent of surgery in carriers of PVs in BC predisposition genes. Citation Format: Judy C. Boughey, Tanya L. Hoskin, Siddhartha Yadav, Fergus J. Couch. The influence of pathogenic variants in breast cancer predisposition genes on secondary breast cancer events in a prospectively collected cohort of breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-02.

Abstract Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success <85%), maximum time in trial (2 years) or for safety as recommended by the independent DSMB. Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-10.

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. We have previously observed in the I-SPY 2 TRIAL that while metastatic events outside the central nervous system (CNS) were dramatically reduced in the setting of pCR, the incidence of CNS metastasis remained similar across RCB classes, raising the possibility that these CNS events may be independent of response in the breast. In this study, we evaluate the type and sites of recurrences by RCB in a large pooled dataset, which allows for analysis within subtype, to validate these findings. Methods: 5161 patients pooled across 12 institutions/trials with available RCB and event-free survival (EFS) data were included in this analysis. EFS was calculated as the interval between treatment initiation, and locoregional recurrence, distant recurrence or death from any cause; patients without event are censored at time of last follow-up. The median follow-up is 4.6 years. We summarized the EFS event type, further sub-dividing the distant recurrence events (DR) by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We used a competing risk (Fine-Gray) model to assess which of these site-specific relapses differ between RCB classes and estimated the cumulative incidence of CNS-only and non-CNS events at 5 years. Analyses were performed across the entire study population and within HR/HER2 defined subtypes. Results: Among the 5161 subjects, there were 1164 EFS events, including 92 (7.9%) local recurrences (without distant recurrence and/or death) and 1072 distant recurrence-free survival (DRFS) events. Among the DRFS events, 158 patients died without a distant recurrence. 914 experienced distant recurrences, including 90 (9.8%) with CNS-only, 145 (15.9%) with CNS and other sites, 664 (72.6%) with non-CNS distant recurrence; 15 (1.6%) patients had missing recurrence site information. Table 1 summarizes the cumulative incidence of CNS-only and non-CNS recurrence at 5 years and the proportion of CNS-only recurrences among DR events by RCB class overall and within each HR/HER2 subtypes. The incidence of CNS-only recurrences was low and similar across RCB classes. In contrast, the incidence of non-CNS recurrences increases with increasing RCB. As a result, CNS-only recurrences are proportionally higher within the RCB-0 and RCB-I than in the RCB-II and RCB-III groups, largely because of the low DR event rate and relative low frequency of non-CNS recurrence events within the RCB-0 and RCB-I classes. Overall, 27% of the recurrences in the setting of pCR (RCB-0) are due to CNS-only recurrences.Conclusions: Consistent with previous studies, our large pooled analysis confirmed that CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings suggest that inclusion of CNS-only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcomes in the context of current therapies. Novel therapies that cross the blood brain barrier will be needed to impact CNS recurrence rates. Table 1: Cumulative Incidence of CNS Only and non-CNS Distant Recurrences at 5 years and proportion of CNS-only events among DR eventsRCB Class0IIIIIIpOverall (5161)N16766622017806Cum. Inc. CNS Only2%2%2%1%0.627Cum. Inc. Non-CNS3%6%16%27%<0.001# CNS-Only / # DR events (%)26/96 (27%)14/74 (19%)39/443 (9%)11/301 (4%)HR-HER2- (1774)N770212590202Cum. Inc. CNS Only2%3%2%4%0.298Cum. Inc. Non-CNS4%11%19%42%<0.001# CNS-Only / # DR events (%)13/50 (26%)6/32 (19%)13/148 (9%)8/111 (7%)HR-HER2+ (572)N3766710029Cum. Inc. CNS Only1%5%5%0%0.022Cum. Inc. Non-CNS2%5%18%38%<0.001# CNS-Only / # DR events (%)4/17 (24%)3/10 (30%)6/31 (19%)0/13 (0%)HR+HER2+ (858)N31317229182Cum. Inc. CNS Only1%1%2%0%0.37Cum. Inc. Non-CNS2%3%15%26%<0.001# CNS-Only / # DR events (%)3/10 (30%)2/16 (12%)7/68 (10%)0/29 (0%)HR+HER2- (1957)N2172111036493Cum. Inc. CNS Only3%2%1%0.2%0.087Cum. Inc. Non-CNS5%4%13%20%<0.001# CNS-Only / # DR events (%)6/19 (32%)3/16 (19%)13/196 (7%)3/148 (2%) Citation Format: Sonal Shad, Marieke van der Noordaa, Marie Osdoit, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Miguel Martin, María Del Monte-Millán, Sara López-Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Gabe Sonke, Tessa G Steenbruggen, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephen Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fan Fang, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberly Cole, Lajos Pusztai, Laura Van't Veer, Fraser Symmans, Laura Esserman, Christina Yau. Site of recurrence after neoadjuvant therapy: A multi-center pooled analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-02.

Abstract Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with breast cancer is associated with improved survival. Further assessment of the extent of residual disease, using the pathological anatomic American Joint Committee on Cancer staging method (ypStage) or the Residual Cancer Burden (RCB) method, have been shown to add prognostic information for patients with residual disease. Neo-Bioscore, an alternate system to classify response to NAC, includes clinical stage at diagnosis and biology and defines eight prognostic groups. The goal of this study was to compared three scoring systems (anatomic ypStage (7th ed), RCB Class and Neo-Bioscore) and assess whether RCB Class and Neo-Bioscore provide additional prognostic value in the context above anatomic ypStage, the most commonly used method for post-neoadjuvant residual disease assessment. Methods: Data from 5161 patients treated with NAC was pooled from 12 sites. Patients without clinical and pathological staging were excluded, as were patients with HER2+ breast cancer who did not receive neoadjuvant HER2-targeted therapy, leaving 3730 for analysis. PCR was defined as no residual invasive tumor in breast and nodes, i.e. RCB-0 or ypT0/Tis and ypN0. Patients with discordant pCR status by RCB Class vs ypStage (n=9) were excluded. Associations between each scoring system and event-free survival (EFS) were evaluated using the log rank test. EFS at 5 years was estimated using the Kaplan Meier method. Associations between Neo-Bioscore and EFS were assessed in the pCR group. For patients with residual disease, we assessed RCB and Neo-Bioscore within each ypStage. Analysis was performed overall and within subtype. Subgroups with <5 patients were excluded from the survival analyses. Results: ypAJCC staging, RCB class and Neo-Bioscore were all associated with EFS in the overall population and within each subtype (log rank p<0.0001). Of note, 13 patients with a Neo-Bioscore of 7 all recurred or died within 19 months of follow-up. Overall, 34% (1264/3721) of patients achieved a pCR. Their Neo-Bioscore ranges from 0-5, where 3% (37/1264) has a Neo-Bioscore of 5 despite achieving pCR. The Neo-Bioscore was not associated with EFS in case of a pCR, with EFS estimates at 5 years of 95%, 94%, 92%, 93%, 90% and 92% for Neo-Bioscores 0-5 respectively. As HR and HER2 status are components of the score, the range of Neo-Bioscore in the pCR group differs by subtype. However, similar to the overall analysis, the Neo-Bioscore was not prognostic within subtypes in case of pCR. Overall, among the patients who did not achieve pCR, both RCB class and Neo-Bioscore were associated with EFS within ypStages I, II and III. However, the ypStage within which RCB and Neo-Bioscore are prognostic is different for each subtype. RCB class was prognostic in ypStage I in both HR+ subtypes: patients with ypStage-I/RCB-I had significantly improved survival compared to patients with ypStage-I/RCB-II (5-year EFS: 100% vs 83% in HR+HER2- and 95% vs 77% in HR+HER2+). In contrast, for patients with triple negative breast cancer, RCB class was prognostic within ypStage II and III. Analysis by clinical stage and the components of the three systems that contribute most to prognosis will be presented. Conclusions: The degree of response to NAC adds important information to pCR versus residual disease. The Neo-Bioscore was not prognostic among patients with pCR, suggesting that clinical stage (including subtype and grade) adds little information in the setting of a pCR. In contrast, both RCB and Neo-Bioscore provide additional prognostic information to the conventional ypAJCC staging among non-pCR patients, suggesting that clinical stage, tumor biology as well as extent of residual disease all contribute to prognosis in the setting of residual disease after NAC. Citation Format: Marieke EM van der Noordaa, Christina Yau, Sonal Shad, Marie Osdoit, Tessa G Steenbruggen, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Maria Del Monte-Millán, Miguel Martin, Sara Lopez Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew Goetz, Tanya Hoskin, Rebecca Gould, Vincent Valero, Gabe Sonke, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephan Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna MacKintosh, Fang Fan, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberley Cole, Lajos Pusztai, Laura van 't Veer, Fraser Symmans, Laura Esserman. Assessing prognosis after neoadjuvant therapy: A comparison between anatomic ypAJCC staging, residual cancer burden class and neo-bioscore [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-07.

Abstract Background: With few targeted therapies available for triple-negative breast cancer (TNBC), there is a critical need to identify biomarkers that can predict chemotherapy-response. Copy number amplifications (CNAmps) have been implicated in tumorigenesis, progression, and treatment response. Previously, we performed a prospective neoadjuvant chemotherapy study (BEAUTY) and identified a 5 Mb CNAmp in TNBC patients associated with pathological complete response rates to taxane- and anthracycline-based chemotherapy. Here we further interrogated this amplicon and its role in chemotherapy response. Methods: Using siRNA screening of genes identified in the 5 Mb CNAmp, followed by cytotoxicity assays, we identified RDH10 significantly associated with chemo-sensitivity in TNBC cell lines. Functional studies were performed using RDH10 knockdown or overexpression followed by cytotoxicity, cell proliferation, luciferase reporter assays, HPLC or western blot. Results: RDH10 is a rate-limiting step involved in the synthesis of all-trans retinoic acid (ATRA) - the active metabolite of retinoid metabolism that is frequently aberrant in cancer. Previous studies demonstrated ATRA to be a potent inhibitor of PIN1, a key regulator of several oncogenic signaling pathways often amplified in TNBC. We discovered that genetic manipulation of RDH10 affected ATRA intracellular concentrations, contributing to PIN1 degradation and taxane-response. Furthermore, co-treatment of TNBC cells with ATRA significantly increased taxane-sensitivity. Conclusion: RDH10 amplification increases endogenous levels of ATRA and degrades PIN1 in TNBC. ATRA-mediated degradation of PIN1 sensitizes TNBC to chemotherapy, suggesting that RDH10 may be a novel biomarker of taxane response and the addition of ATRA to standard chemotherapy may improve chemo-sensitivity.

Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus) confirmed activity for 13 drugs (the majority having IC50 < 10 μM), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.

Abstract Purpose: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors—a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. Patients and Methods: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. Results: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35–49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P &lt; 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3–4 adverse events related to low-dose tamoxifen. Conclusions: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Abstract Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.