Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials.

BACKGROUND: Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. METHODS: The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. RESULTS: The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). CONCLUSIONS: In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC.

Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.

Distinct functions of EHMT1 and EHMT2 in cancer chemotherapy and immunotherapy.

EHTM1 (GLP) and EHMT2 (G9a) are closely related protein lysine methyltransferases often thought to function together as a heterodimer to methylate histone H3 and non-histone substrates in diverse cellular processes including transcriptional regulation, genome methylation, and DNA repair. Here we show that EHMT1/2 inhibitors cause ATM-mediated slowdown of replication fork progression, accumulation of single-stranded replication gaps, emergence of cytosolic DNA, and increased expression of STING. EHMT1/2 inhibition strongly potentiates the efficacy of alkylating chemotherapy and anti-PD-1 immunotherapy in mouse models of tripe negative breast cancer. The effects on DNA replication and alkylating agent sensitivity are largely caused by the loss of EHMT1-mediated methylation of LIG1, whereas the elevated STING expression and remarkable response to immunotherapy appear mainly elicited by the loss of EHMT2 activity. Depletion of UHRF1, a protein known to be associated with EHMT1/2 and LIG1, also induces STING expression, and depletion of either EHMT2 or UHRF1 leads to demethylation of specific CpG sites in the STING1 promoter, suggestive of a distinct EHMT2-UHRF1 axis that regulates DNA methylation and gene transcription. These results highlight distinct functions of the two EHMT paralogs and provide enlightening paradigms and corresponding molecular basis for combination therapies involving alkylating agents and immune checkpoint inhibitors.

Promoting informed approaches in precision oncology and clinical trial participation for Black patients with cancer: Community-engaged development and pilot testing of a digital intervention.

BACKGROUND: Black patients with cancer are less likely to receive precision cancer treatments than White patients and are underrepresented in clinical trials. To address these disparities, the study aimed to develop and pilot-test a digital intervention to improve Black patients' knowledge about precision oncology and clinical trials, empower patients to increase relevant discussion, and promote informed decision-making. METHODS: A community-engaged approach, including a Community Advisory Board and two rounds of key informant interviews with Black patients with cancer, their relatives, and providers (n = 48) was used to develop and refine the multimedia digital intervention. Thematic analysis was conducted for qualitative data. The intervention was then pilot-tested with 30 Black patients with cancer to assess feasibility, acceptability, appropriateness, knowledge, decision self-efficacy, and patient empowerment; Wilcoxon matched pairs signed-rank test was used to analyze quantitative data. RESULTS: The digital tool was found to be feasible, acceptable, and culturally appropriate. Key informants shared their preferences and recommendations for the digital intervention and helped improve cultural appropriateness through user and usability testing. In the pilot test, appreciable improvement was found in participants' knowledge about precision oncology (z = -2.04, p = .052), knowledge about clinical trials (z = -3.14, p = .001), and decisional self-efficacy for targeted/immune therapy (z = -1.96, p = .0495). CONCLUSIONS: The digital intervention could be a promising interactive decision-support tool for increasing Black patients' participation in clinical trials and receipt of precision treatments, including immunotherapy. Its use in clinical practice may reduce disparities in oncology care and research. PLAIN LANGUAGE SUMMARY: We developed a digital interactive decision support tool for Black patients with cancer by convening a Community Advisory Board and conducting interviews with Black patients with cancer, their relatives, and providers. We then pilot-tested the intervention with newly diagnosed Black patients with cancer and found appreciable improvement in participants' knowledge about precision oncology, knowledge about clinical trials, and confidence in making decisions for targeted/immune therapy. Our digital tool has great potential to be an affordable and scalable solution for empowering and educating Black patients with cancer to help them make informed decisions about precision oncology and clinical trials and ultimately reducing racial disparities.

Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study.

PURPOSE: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC). METHODS: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA. RESULTS: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC. CONCLUSION: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.

Integrated metabolic and genetic analysis reveals distinct features of human differentiated thyroid cancer.

BACKGROUND: Differentiated thyroid cancer (DTC) affects thousands of lives worldwide each year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) quality of life and might be unnecessary in indolent DTC cases. On the other hand, the lack of biomarkers indicating a potential metastatic thyroid cancer imposes an additional challenge to managing and treating patients with this disease. AIM: The presented clinical setting highlights the unmet need for a precise molecular diagnosis of DTC and potential metastatic disease, which should dictate appropriate therapy. MATERIALS AND METHODS: In this article, we present a differential multi-omics model approach, including metabolomics, genomics, and bioinformatic models, to distinguish normal glands from thyroid tumours. Additionally, we are proposing biomarkers that could indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. RESULTS: Normal and tumour thyroid tissue from DTC patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumour cells. The consistency of the DTC metabolic profile allowed us to build a bioinformatic classification model capable of clearly distinguishing normal from tumor thyroid tissues, which might help diagnose thyroid cancer. Moreover, based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intra-tumour heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. DISCUSSION: Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. CONCLUSIONS: Well-designed, prospective translational clinical trials will ultimately show the value of this integrated multi-omics approach and early diagnosis of DTC and potential metastatic PTC.

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.

Computational pathology improves risk stratification of a multi-gene assay for early stage ER+ breast cancer.

Prognostic markers currently utilized in clinical practice for estrogen receptor-positive (ER+) and lymph node-negative (LN-) invasive breast cancer (IBC) patients include the Nottingham grading system and Oncotype Dx (ODx). However, these biomarkers are not always optimal and remain subject to inter-/intra-observer variability and high cost. In this study, we evaluated the association between computationally derived image features from H&E images and disease-free survival (DFS) in ER+ and LN- IBC. H&E images from a total of n = 321 patients with ER+ and LN- IBC from three cohorts were employed for this study (Training set: D1 (n = 116), Validation sets: D2 (n = 121) and D3 (n = 84)). A total of 343 features relating to nuclear morphology, mitotic activity, and tubule formation were computationally extracted from each slide image. A Cox regression model (IbRiS) was trained to identify significant predictors of DFS and predict a high/low-risk category using D1 and was validated on independent testing sets D2 and D3 as well as within each ODx risk category. IbRiS was significantly prognostic of DFS with a hazard ratio (HR) of 2.33 (95% confidence interval (95% CI) = 1.02-5.32, p = 0.045) on D2 and a HR of 2.94 (95% CI = 1.18-7.35, p = 0.0208) on D3. In addition, IbRiS yielded significant risk stratification within high ODx risk categories (D1 + D2: HR = 10.35, 95% CI = 1.20-89.18, p = 0.0106; D1: p = 0.0238; D2: p = 0.0389), potentially providing more granular risk stratification than offered by ODx alone.

SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity.

The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the KrasG12D-driven mouse LUAD model, we found that loss of Sox9 significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice. We demonstrate that SOX9 suppresses immune cell infiltration and functionally suppresses tumor associated CD8+ T, natural killer and dendritic cells. These data were validated by flow cytometry, gene expression, RT-qPCR, and immunohistochemistry analyses in KrasG12D-driven murine LUAD, then confirmed by interrogating bulk and single-cell gene expression repertoires and immunohistochemistry in human LUAD. Notably, SOX9 significantly elevates collagen-related gene expression and substantially increases collagen fibers. We propose that SOX9 increases tumor stiffness and inhibits tumor-infiltrating dendritic cells, thereby suppressing CD8+ T cell and NK cell infiltration and activity. Thus, SOX9 drives KrasG12D-driven lung tumor progression and inhibits anti-tumor immunity at least partly by modulating the tumor microenvironment.

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

BACKGROUND: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. RESULTS: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. CONCLUSION: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

Integrated metabolic and genetic analysis reveals distinct features of primary differentiated thyroid cancer and its metastatic potential in humans.

Differentiated thyroid cancer (DTC) affects thousands of lives worldwide every year. Typically, DTC is a treatable disease with a good prognosis. Yet, some patients are subjected to partial or total thyroidectomy and radioiodine therapy to prevent local disease recurrence and metastasis. Unfortunately, thyroidectomy and/or radioiodine therapy often worsen(s) the quality of life and might be unnecessary in indolent DTC cases. This clinical setting highlights the unmet need for a precise molecular diagnosis of DTC, which should dictate appropriate therapy. Here we propose a differential multi-omics model approach to distinguish normal gland from thyroid tumor and to indicate potential metastatic diseases in papillary thyroid cancer (PTC), a sub-class of DTC. Based on PTC patient samples, our data suggest that elevated nuclear and mitochondrial DNA mutational burden, intratumor heterogeneity, shortened telomere length, and altered metabolic profile reflect the potential for metastatic disease. Specifically, normal and tumor thyroid tissues from these patients had a distinct yet well-defined metabolic profile with high levels of anabolic metabolites and/or other metabolites associated with the energy maintenance of tumor cells. Altogether, this work indicates that a differential and integrated multi-omics approach might improve DTC management, perhaps preventing unnecessary thyroid gland removal and/or radioiodine therapy. Well-designed, prospective translational clinical trials will ultimately show the value of this targeted molecular approach. TRANSLATIONAL RELEVANCE: In this article, we propose a new integrated metabolic, genomic, and cytopathologic methods to diagnose Differentiated Thyroid Cancer when the conventional methods failed. Moreover, we suggest metabolic and genomic markers to help predict high-risk Papillary Thyroid Cancer. Both might be important tools to avoid unnecessary surgery and/or radioiodine therapy that can worsen the quality of life of the patients more than living with an indolent Thyroid nodule.

Uveitis, a rare but important complication of adjuvant zoledronic acid for early-stage breast cancer.

Bisphosphonates such as zoledronic acid are an important part of adjuvant therapy to reduce the risk of recurrence in early-stage breast cancer. Uveitis remains one of the lesser-known side effects of zoledronic acid; prompt recognition is essential to ensure patients receive appropriate and timely care to help prevent permanent vision loss. We report a case of anterior uveitis in a postmenopausal woman who presented with visual symptoms after receiving the first dose of zoledronic acid. This case report serves to educate and increase awareness of the risk of uveitis in patients who are given zoledronic acid. This is the first and only reported case of zoledronic acid when used in the adjuvant setting for the treatment of breast cancer.

Evaluation of Inequities in Cancer Treatment Delay or Discontinuation Following SARS-CoV-2 Infection.

Importance: There is a disproportionately greater burden of COVID-19 among Hispanic and non-Hispanic Black individuals, who also experience poorer cancer outcomes. Understanding individual-level and area-level factors contributing to inequities at the intersection of COVID-19 and cancer is critical. Objective: To evaluate associations of individual-level and area-level social determinants of health (SDOH) with delayed or discontinued cancer treatment following SARS-CoV-2 infection. Design, Setting, and Participants: This retrospective, registry-based cohort study used data from 4768 patients receiving cancer care who had positive test results for SARS-CoV-2 and were enrolled in the American Society for Clinical Oncology COVID-19 Registry. Data were collected from April 1, 2020, to September 26, 2022. Exposures: Race and ethnicity, sex, age, and area-level SDOH based on zip codes of residence at the time of cancer diagnosis. Main Outcomes and Measures: Delayed (≥14 days) or discontinued cancer treatment (any cancer treatment, surgery, pharmacotherapy, or radiotherapy) and time (in days) to restart pharmacotherapy. Results: A total of 4768 patients (2756 women [57.8%]; 1558 [32.7%] aged ≥70 years at diagnosis) were included in the analysis. There were 630 Hispanic (13.2%), 196 non-Hispanic Asian American or Pacific Islander (4.1%), 568 non-Hispanic Black (11.9%), and 3173 non-Hispanic White individuals (66.5%). Compared with non-Hispanic White individuals, Hispanic and non-Hispanic Black individuals were more likely to experience a delay of at least 14 days or discontinuation of any treatment and drug-based treatment; only estimates for non-Hispanic Black individuals were statistically significant, with correction for multiple comparisons (risk ratios [RRs], 1.35 [95% CI, 1.22-1.49] and 1.37 [95% CI, 1.23-1.52], respectively). Area-level SDOH (eg, geography, proportion of residents without health insurance or with only a high school education, lower median household income) were associated with delayed or discontinued treatment. In multivariable Cox proportinal hazards regression models, estimates suggested that Hispanic (hazard ratio [HR], 0.87 [95% CI, 0.71-1.05]), non-Hispanic Asian American or Pacific Islander (HR, 0.79 [95% CI, 0.46-1.35]), and non-Hispanic Black individuals (HR, 0.81 [95% CI, 0.67-0.97]) experienced longer delays to restarting pharmacotherapy compared with non-Hispanic White individuals. Conclusions and Relevance: The findings of this cohort study suggest that race and ethnicity and area-level SDOH were associated with delayed or discontinued cancer treatment and longer delays to the restart of drug-based therapies following SARS-CoV-2 infection. Such treatment delays could exacerbate persistent cancer survival inequities in the United States.

Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

Subtype and cell type specific expression of lncRNAs provide insight into breast cancer.

Long non-coding RNAs (lncRNAs) are involved in breast cancer pathogenesis through chromatin remodeling, transcriptional and post-transcriptional gene regulation. We report robust associations between lncRNA expression and breast cancer clinicopathological features in two population-based cohorts: SCAN-B and TCGA. Using co-expression analysis of lncRNAs with protein coding genes, we discovered three distinct clusters of lncRNAs. In silico cell type deconvolution coupled with single-cell RNA-seq analyses revealed that these three clusters were driven by cell type specific expression of lncRNAs. In one cluster lncRNAs were expressed by cancer cells and were mostly associated with the estrogen signaling pathways. In the two other clusters, lncRNAs were expressed either by immune cells or fibroblasts of the tumor microenvironment. To further investigate the cis-regulatory regions driving lncRNA expression in breast cancer, we identified subtype-specific transcription factor (TF) occupancy at lncRNA promoters. We also integrated lncRNA expression with DNA methylation data to identify long-range regulatory regions for lncRNA which were validated using ChiA-Pet-Pol2 loops. lncRNAs play an important role in shaping the gene regulatory landscape in breast cancer. We provide a detailed subtype and cell type-specific expression of lncRNA, which improves the understanding of underlying transcriptional regulation in breast cancer.

Breaking satellite silence: human satellite II RNA expression in ovarian cancer.

Multiple cancer types demonstrate abnormal expression of repetitive RNA sequences as a form of epigenetic instability. There is growing interest in understanding the role of repetitive RNAs in cancer pathogenesis and immunogenicity and in their potential role as diagnostic or therapeutic biomarkers. In this issue of the JCI, Porter and colleagues report on satellite RNA in a subset of ovarian cancers. The authors found that high expression of human satellite (HSAT) repeats - but not other families of repeats - was associated with an immunosuppressive phenotype in ovarian cancer cell lines and tumor samples. Further induction of HSAT RNA levels in vitro, surprisingly, leads to innate immune activation, suggesting a potential therapeutic strategy. This work highlights the expanding role of repetitive RNAs in tumor biology and the need to better define specific classes of repetitive elements expressed in cancer - as well as their role in tumorigenesis, tumor immunity, and the host response to cancer.

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial.

Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.

Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice.

The BRCA1-PALB2-BRCA2 axis, or the BRCA pathway, plays key roles in genome stability maintenance and suppression of breast and several other cancers. Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brca1, Brca2 and Palb2 conditional knockout models, it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis. Here, we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds. Rather than mammary tumors, Palb2 and Trp53 compound mutant mice developed, with greatly reduced latencies, lymphomas and sarcomas that are typically associated with germline Trp53 inactivation. Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice. These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development, possibly without altering the fundamental tumorigenic processes.