Statins Do Not Significantly Affect Oxidative Nitrosative Stress Biomarkers in the PREVENT Randomized Clinical Trial.

PURPOSE: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT. PATIENTS AND METHODS: Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine-nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF. RESULTS: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05). CONCLUSIONS: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.

Adverse Cardiovascular Events Associated With Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Metastatic Breast Cancer.

Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.

PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies.

BACKGROUND: Breast cancer mortality is principally due to recurrent disease that becomes resistant to therapy. We recently identified copy number (CN) gain of the putative membrane progesterone receptor PAQR8 as one of four focal CN alterations that preferentially occurred in recurrent metastatic tumors compared to primary tumors in breast cancer patients. Whether PAQR8 plays a functional role in cancer is unknown. Notably, PAQR8 CN gain in recurrent tumors was mutually exclusive with activating ESR1 mutations in patients treated with anti-estrogen therapies and occurred in > 50% of both patients treated with anti-estrogen therapies and those treated with chemotherapy or anti-Her2 agents. METHODS: We used orthotopic mouse models to determine whether PAQR8 overexpression or deletion alters breast cancer dormancy or recurrence following therapy. In vitro studies, including assays for colony formation, cell viability, and relative cell fitness, were employed to identify effects of PAQR8 in the context of therapy. Cell survival and proliferation were quantified by immunofluorescence staining for markers of apoptosis and proliferation. Sphingolipids were quantified by liquid chromatography-high resolution mass spectrometry. RESULTS: We show that PAQR8 is necessary and sufficient for efficient mammary tumor recurrence in mice, spontaneously upregulated and CN gained in recurrent tumors that arise following therapy in multiple mouse models, and associated with poor survival following recurrence as well as poor overall survival in breast cancer patients. PAQR8 promoted resistance to therapy by enhancing tumor cell survival following estrogen receptor pathway inhibition by fulvestrant or estrogen deprivation, Her2 pathway blockade by lapatinib or Her2 downregulation, and treatment with chemotherapeutic agents. Pro-survival effects of PAQR8 were mediated by a Gi protein-dependent reduction in cAMP levels, did not require progesterone, and involved a PAQR8-dependent decrease in ceramide levels and increase in sphingosine-1-phosphate levels, suggesting that PAQR8 may possess ceramidase activity. CONCLUSIONS: Our data provide in vivo evidence that PAQR8 plays a functional role in cancer, implicate PAQR8, cAMP, and ceramide metabolism in breast cancer recurrence, and identify a novel mechanism that may commonly contribute to the acquisition of treatment resistance in breast cancer patients.

Acute skin radiation toxicity seen with concurrent T-DM1: A single institutional report of 35 patients.

Trastuzumab emtansine (T-DM1) is a novel therapeutic for HER2+ breast cancer patients with residual disease after neoadjuvant chemotherapy. Concurrent radiotherapy (RT) is offered to a subset of patients based on results from the KATHERINE trial which showed a favorable safety profile. With emerging therapies that necessitate concurrent RT, we must closely follow rates of skin toxicity. Our first 35 patients who underwent concurrent T-DM1 treatment with breast/chest wall (CW) ± nodal irradiation are reported. Most patients (22/35) had grade 2+ toxicity and 3 patients had grade 3 toxicities. We add our experience with radiation dermatitis and concurrent T-DM1 to contribute to existing reports.

Ruxolitinib and exemestane for estrogen receptor positive, aromatase inhibitor resistant advanced breast cancer.

Circulating IL-6, an activator of JAK/STAT signaling, is associated with poor prognosis and aromatase inhibitor (AI) resistance in hormone-receptor positive (HR+) breast cancer. Here we report the results of a phase 2 single-arm Simon 2-stage trial combining Ruxolitinib, an oral selective inhibitor of JAK1/2, with exemestane, a steroidal AI, in patients with HR+ metastatic breast cancer (MBC) after progression on non-steroidal AI (NSAI). Safety and efficacy were primary objectives, and analysis of inflammatory markers as predictors of response was a key secondary objective. Twenty-five subjects enrolled. The combination of ruxolitinib and exemestane was safe, though anemia requiring transfusion in 5/15 (33%) at the 25 mg dose in stage 1 led to a reduction to 15 mg twice daily in stage 2 (with no additional transfusions). Clinical benefit rate (CBR) in the overall study population was 24% (95% CI 9.4-45.1); 6/25 patients demonstrated stable disease for ≥6 months. Median progression-free survival was 2.8 months (95% CI 2.6-3.9). Exploratory biomarkers revealed high levels of systemic inflammation and 60% harbored a high-risk IL-6 genotype. Pharmacodynamics demonstrated modest on-target inhibition of phosphorylated-STAT3 by ruxolitinib at a tolerable dose. Thus, ruxolitinib combined with exemestane at a tolerable dose was safe but minimally active in AI-resistant tumors of patients with high levels of systemic inflammation. These findings highlight the need for more potent and specific therapies targeting inflammation in MBC.

18F-FDG PET/CT for the Evaluation of Therapy Response in Hormone Receptor-Positive Bone-Dominant Metastatic Breast Cancer.

Fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT has shown promise for use in assessing treatment response in patients with bone-only or bone-dominant (BD) metastatic breast cancer (mBC). In this single-institution, prospective single-arm study of 23 women (median age, 59 years [range, 38-81 years]) with biopsy-proven estrogen receptor-positive bone-only or BD mBC about to begin new endocrine therapy between October 3, 2013, and August 3, 2018, the value of early 4-week 18F-FDG PET/CT in predicting progression-free survival (PFS) was evaluated. 18F-FDG PET/CT was performed at baseline, 4 weeks, and 12 weeks. Maximum standardized uptake value (SUVmax) and peak SUV (SUVpeak) were measured for up to five index lesions. The primary end point was PFS. Secondary end points were overall survival (OS) and time to skeletal-related events (tSREs). All end points were compared between responders (reduction of 30% or more in the sum of SUVmax for target lesions) and nonresponders at 4 weeks and 12 weeks. Percentage change from baseline in SUVmax at 4- and 12-week 18F-FDG PET/CT were highly correlated (r = 0.81). At the 4-week time point PET responders had numerically longer PFS (14.2 months vs 6.3 months; P = .53), OS (44.0 months vs 29.7 months; P = .47), and tSRE (27.4 months vs 25.2 months; P = .66) compared with nonresponders, suggesting the clinical utility of 4-week 18F-FDG PET/CT as an early predictor of treatment failure. Keywords: Breast Cancer, Metastatic Breast Cancer, Bone-Dominant Metastatic Breast Cancer, FDG PET/CT, Estrogen-Receptor Positive Metastatic Breast Cancer Supplemental material is available for this article. Clinical trial registration no. NCT04316117 © RSNA, 2022.

Trastuzumab deruxtecan: An antibody-drug conjugate embracing its destiny in breast cancer.

In DESTINY-Breast 03, Trastuzumab Deruxtecan, a HER2-specific antibody-drug conjugate, proved superior to T-DM1 in patients with HER2+ metastatic breast cancer progressing on taxane and trastuzumab.1 This study supported its recent approval as second-line therapy in HER2+ metastatic breast cancer.

Germline ERBB2/HER2 Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms.

Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the ERBB2/HER2 gene that co-segregates with disease. To further investigate whether germline ERBB2 variants contribute to MPN predisposition, the frequency of ERBB2 variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline ERBB2 coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, p = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, p = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, p = 0.040). The most frequent variant identified, ERBB2 c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in ERBB2 are associated with an increased risk for development of MPN. The ERBB2 gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles.

Setting the Pick: Can PI3K Inhibitors Circumvent CDK4/6 Inhibitor Resistance?

PI3K and CDK4/6 inhibitors (CDK4/6i) are targeted therapies approved to treat advanced breast cancer; CDK4/6is are more widely used. Here, we discuss trials that examine PI3K inhibitors with novel drug combinations, including a CDK4/6i, given data implicating the pathway in CDK 4/6 resistance.See related articles by Lu et al., p. 408, and Tolaney et al., p. 418.

Oligometastatic Breast Cancer: Is This a Curable Entity? A Contemporary Review of the Literature.

PURPOSE OF REVIEW: Oligometastatic breast cancer (OMBC) remains a poorly understood entity for which no standard of care exists at this time. This review will focus on our biologic understanding of OMBC and provide an update on current treatment strategies. RECENT FINDINGS: The introduction of micro RNA expression profiling has advanced our understanding of the biologic underpinnings of OMBC. Although most of the data regarding treatment have come from retrospective studies, there are now prospective randomized trials reporting progression-free survival and overall survival improvements with stereotactic ablative radiotherapy (SABR). Ongoing studies designed to evaluate addition of SABR as well as other novel agents will further develop this field and provide new treatment options. A "cure" for OMBC remains elusive. With further basic research coupled with novel prospective trials, patients will hopefully enjoy increased progression-free survival and overall survival, and ideally a delay to more toxic systemic therapy.

Clinical activity of the EGFR tyrosine kinase inhibitor osimertinib in EGFR-mutant glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The EGFR gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated EGFR-mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the EGFR mutations relevant in GBM.

Germline mutations in the alternative pathway of complement predispose to HELLP syndrome.

BACKGROUND: HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is a severe variant of hypertensive disorders of pregnancy affecting approximately 1% of all pregnancies, and has significant maternal and fetal morbidity. Previously, we showed that upregulation of the alternative pathway of complement (APC) plays a role in HELLP syndrome. We hypothesize that HELLP syndrome follows a 2-hit disease model similar to atypical hemolytic uremic syndrome (aHUS), requiring both genetic susceptibility and an environmental risk factor. Our objective was to perform a comparative analysis of the frequency of APC activation and germline mutations in affected women and to create a predictive model for identifying HELLP syndrome. METHODS: Pregnant women with HELLP syndrome, and healthy controls after 23 weeks of gestation were recruited, along with aHUS and thrombotic thrombocytopenic purpura participants. We performed a functional assay, the mHam, and targeted genetic sequencing in all groups. RESULTS: Significantly more participants with rare germline mutations in APC genes were present in the HELLP cohort compared with controls (46% versus 8%, P = 0.01). In addition, significantly more HELLP participants were positive for the mHam when compared with controls (62% versus 16%, P = 0.009). Testing positive for both a germline mutation and the mHam was highly predictive for the diagnosis of HELLP syndrome. CONCLUSION: HELLP syndrome is characterized by both activation of the APC and frequent germline mutations in APC genes. Similar to aHUS, treatment via complement inhibition to mitigate maternal and fetal morbidity and mortality may be possible. FUNDING: National Heart Lung and Blood Institute grants T32HL007525 and R01HL133113.

The mTOR pathway affects proliferation and chemosensitivity of urothelial carcinoma cells and is upregulated in a subset of human bladder cancers.

OBJECTIVE: To investigate whether mammalian target of rapamycin (mTOR) inhibition by rapamycin is therapeutically efficacious in combination with cisplatin for bladder cancer. MATERIALS AND METHODS: Using a panel of human urothelial carcinoma cell lines, we determined the effect of rapamycin on cell viability, cell-cycle progression, signalling and apoptosis. The effect of mTOR inhibition on chemosensitivity was investigated by treating cells with rapamycin, alone, or with cisplatin. The effect of rapamycin or cisplatin treatment was assessed in xenograft mice inoculated with urothelial carcinoma cells. Expression of p-mTOR in human bladder cancer specimens was assessed using a tissue microarray. RESULTS: Treatment with rapamycin significantly decreased cell viability in UMUC3 (P = 0.004) and 253J (P < 0.001) cells. It induced arrest in the G(0) -G(1) phase and decreased activation of p-mTOR and its downstream effector, p-S6K, in both cell lines. Treatment with rapamycin increased the ability of cisplatin to inhibit cell viability in UMUC3 (P = 0.002) and 253J (P = 0.03) cells. No evidence for apoptosis induction was noted after treatment with rapamycin alone. Mouse xenografts of UMUC3 cells revealed that rapamycin significantly prolonged survival and enhanced the therapeutic efficacy of cisplatin. In patient urothelial carcinoma specimens, p-mTOR expression was increased in cancer vs non-tumour bladder tissue in 65/203 (32.0%) tumours. CONCLUSIONS: mTOR blockade inhibits urothelial carcinoma cell proliferation and enhances the effectiveness of cisplatin. Suppression of the mTOR pathway has the potential to be a therapeutic target in bladder cancer for selected patients.