Citations

Abstract Introduction DISTINCT is a randomized controlled trial evaluating passive recharge burst SCS compared with CMM in improving pain and pain‐related physical function in patients suffering from chronic back pain without prior lumbar surgery, and for whom corrective surgery is not an option. Sub‐analyses of outcome measures are presented for a subset implanted with paddle leads at both 6 and 12 months. Objective To investigate the treatment effect of using BurstDR‐capable SCS in nonsurgical low back pain (NSLBP) patients with paddle leads. Methods An independent board‐certified spine surgeon reviewed each case, confirming a lack of corrective surgical options. Out of 29 sites and 115 implants, 10 sites implanted 50 patients with paddle leads. Primary and secondary endpoints assessed improvements in low back pain intensity (NRS), low back pain‐related disability (ODI), pain catastrophizing (PCS), and patient global impression of change (PGIC). Results Data for patients with NSLBP and implanted with paddle leads are available for 47 and 44 patients at 6 and 12 months, respectively. Patients reported significant reductions in pain relief at 6 and 12 months, decreasing from 7.8 ± 1.2 at baseline to 2.0 ± 1.6 and 2.2 ± 2.2, respectively ( p < 0.0001). Disability was substantially reduced (> 20 points) from severe to mild at 6 and 12 months; ODI reduced from 54.4 ± 15.0 at baseline to 19.9 ± 14.1 and 22.1 ± 13.6, respectively ( p < 0.0001). Pain catastrophizing improved to reflect the average of a non‐chronic pain population; decreased from 27.6 ± 13.1 at baseline to 8.1 ± 8.2 and 7.8 ± 9.9 ( p < 0.0001). 93.2% of patients reported a moderately better‐much‐improved outcome on PGIC. Ten complications occurred in 9 patients, 3 being severe device‐related events. Two explants were required; one due to infection and one due to persistent pain at the IPG site, and one lead‐related event was resolved by surgical repositioning. Conclusions Passive recharge burst using paddle leads provides substantial relief to patients suffering from severe, debilitating, NSLBP. Patients report significant improvements in pain, function, and pain‐related emotional distress. In addition, the rate of adverse events is low, supporting a favorable safety profile.

Abstract Chemotherapy regimens for triple-negative breast cancer (TNBC) combine agents without knowing which agents drive response. Consequently, predictors derived from multi-agent regimens cannot be assumed to generalize to individual drugs or other regimens, motivating development of treatment-matched predictors. Here, we used TNBC patient-derived xenografts (PDXs) treated with carboplatin, docetaxel, or the combination to deconvolute drug-specific responses and identify associated molecular features. Combination treatment rarely improved upon the best single agent, with enhanced responses in only 13% of PDXs and antagonism in a comparable fraction. Proteogenomic analyses identified high cytokeratin-5 (KRT5) as a general marker of chemotherapy responsiveness and KRT5 immunohistochemistry discriminated responsive PDXs (AUROC, 0.83). To train treatment-specific predictors, we integrated these data with independent PDX and clinical cohorts with responses assessed after anthracycline-free platinum, taxane, or platinum-taxane therapy, ensuring response corresponded to the modeled treatment. Four feature selection strategies yielded largely nonoverlapping biomarker panels converging on treatment-relevant pathways. On independent test data, RNA-based predictors of complete response (CR) to platinum-based (carboplatin or cisplatin) and taxane-based (docetaxel or paclitaxel) chemotherapy achieved AUROCs of 0.80 and 0.86, respectively. For platinum-taxane regimens (carboplatin plus docetaxel or paclitaxel), proteomic-guided feature selection generated a 10-biomarker, protein- informed RNA predictor of pathologic complete response (pCR) that outperformed RNA-only feature selection and achieved an AUROC of 0.85 in an independent clinical cohort, while retaining practicality as an RNA-based assay. Treatment-matched integration of multi-omic PDX and clinical datasets provides a framework for chemotherapy-specific predictors with clinically relevant performance, supporting biomarker-guided precision selection and treatment optimization for patients with TNBC. Statement of significance Integration of multi-omic data from patient-derived xenografts with treatment-matched clinical cohorts yielded three retrospectively validated predictors of platinum, taxane, and platinum+taxane response, enabling biomarker-guided chemotherapy selection for patients with triple-negative breast cancer.

Abstract Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.

Abstract Significant endocrine therapy–resistant tumor proliferation is present in ≥20% of estrogen receptor–positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor–resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy–resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168–83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047

Study Design. Prospective cohort study. Objective. To characterize the accuracy of patient recollection of preoperative symptoms after lumbar spine surgery. Summary of Background Data. Although patient-reported outcomes have become important in the evaluation of spine surgery patients, the accuracy of patient recall remains unknown. Methods. Patients undergoing lumbar decompression with or without fusion were enrolled. Back and leg Numeric Pain Scores and Oswestry Disability Indices were recorded preoperatively. Patients were asked to recall their preoperative status at a minimum of 1 year after surgery. Actual and recalled scores were compared using paired t tests and relations were quantified using Pearson correlation coefficients. Multivariable linear regression was used to identify factors that affected recollection. Results. Sixty-two patients with a mean age of 66.1 years were included. Compared to their preoperative scores, patients showed significant improvement in back pain (mean difference [MD] = −3.2, 95% CI −4.0 to −2.4), leg pain (MD −3.3, 95% CI −4.3 to −2.2), and disability (MD −25.0%, 95% CI −28.7 to −19.6). Patient recollection of preoperative status was significantly more severe than actual for back pain (MD +2.3, 95% CI 1.5–3.2), leg pain (MD +1.8, 95% CI 0.9–2.7), and disability (MD +9.6%, 95% CI 5.6–14.0). No significant correlation between actual and recalled scores with regards to back (r = 0.18) or leg (r = 0.24) pain and only moderate correlation with disability (r = 0.44) were seen. This was maintained across age, sex, and time between date of surgery and recollection. More than 40% of patients switched their predominant symptom from back pain to leg pain or leg pain to back pain on recall. Conclusion. Relying on patient recollection does not provide an accurate measure of preoperative status after lumbar spine surgery. Recall bias indicates the importance of obtaining true baseline scores and patient-reported outcomes prospectively and not retrospectively. Level of Evidence: 2