Longitudinal Shifts of Solid Tumor and Liquid Biopsy Sequencing Concordance in Metastatic Breast Cancer.

Tissue-based next-generation sequencing (NGS) in metastatic breast cancer (mBC) is limited by the inability to noninvasively track tumor evolution. Cell-free DNA (cfDNA) NGS has made sequential testing feasible; however, the relationship between cfDNA and tissue-based testing in mBC is not well understood. Here, we evaluate concordance between tissue and cfDNA NGS relative to cfDNA sampling frequency in a large, clinically annotated mBC data set. METHODS: Tempus LENS was used to analyze deidentified records of mBC cases with Tempus xT (tissue) and xF (cfDNA) sequencing results. Then, various metrics of concordance were assessed within overlapping probe regions of the tissue and cfDNA assays (104 genes), focusing on pathogenic variants. Variant allele frequencies of discordant and concordant pathogenic variants were also compared. Analyses were stratified by mBC subtype and time between tests. RESULTS: Records from 300 paired tissue and liquid biopsies were analyzed. Median time between tissue and blood collection was 78.5 days (standard deviation = 642.99). The median number of pathogenic variants/patient was one for cfDNA and two for tissue. Across the cohort, 77.8% of pathogenic tissue variants were found in cfDNA and 75.7% of pathogenic cfDNA variants were found in tissue when tests were ≤ 7 days apart, which decreased to 50.3% and 51.8%, respectively, for > 365 days. Furthermore, the median patient-level variant concordance was 67% when tests were ≤7 days apart and 30%-37% when > 30 days. The median variant allele frequencies of discordant variants were generally lower than those of concordant variants within the same time frame. CONCLUSION: We observed high concordances between tissue and cfDNA results that generally decreased with longer durations between tests. Thus, cfDNA NGS reliably measures tissue genomics and is likely beneficial for longitudinal monitoring of molecular changes in mBC.

Prevalence of Germline Findings Among Tumors From Cancer Types Lacking Hereditary Testing Guidelines.

Importance: Germline testing guidelines are suggested for specific disease types or a family history of cancer, yet alterations are found in cancer types in which germline testing is not routinely indicated. The clinical role of identifying germline variants in these populations is valuable to patients and their at-risk relatives. Objective: To evaluate the prevalence of germline findings in patients undergoing tumor/normal matched sequencing among cancer types lacking guidelines. Design, Setting, and Participants: This retrospective cross-sectional study took place on August 18, 2021, and included data from deidentified records of patients tested, using the Tempus xT tumor/normal matched approach from November 2017 to August 2021. Records included in this study were from 34 642 patients treated in geographically diverse oncology practices in the US with a diagnosis of any of the following cancers: bladder, brain, lung, esophagus, cholangiocarcinoma, head and neck, breast, ovarian, pancreatic, prostate, endometrial, and colorectal. Main Outcomes and Measures: The rate of germline findings (ie, single-nucleotide variants and small insertions or deletions) detected in 50 reportable hereditary cancer genes was calculated for cancer types lacking guidelines for germline testing (bladder, brain, lung, esophagus, cholangiocarcinoma, and head and neck) and cancer types for which germline testing is frequently performed (breast, ovarian, pancreatic, prostate, endometrial, and colorectal). Same-gene second somatic hits were assessed to provide a comprehensive assessment on genomic drivers. Results: Of 34 642 patients, 18 888 were female (54.5%); of 27 498 patients whose age at diagnosis was known, mean (SD) age was 62.23 (3.36) years. A total of 2534 of 34 642 patients (7.3%) harbored pathogenic or likely pathogenic germline variants. Within the tumor types lacking testing guidelines, germline mutations were at 6.6% (79/1188) in bladder cancer and 5.8% (448/7668) in lung cancer. Conclusions and Relevance: This study may present the largest retrospective analysis to date of deidentified real-world data from patients diagnosed with advanced cancer with tumor/normal matched sequencing data and the prevalence of pathogenic or likely pathogenic germline variants in cancer types lacking hereditary cancer testing guidelines. The findings suggest there may be clinical implications for patients and their at-risk family members in cancers for which germline assessment primarily based on the cancer diagnosis is rarely obtained.

Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer ("METRIC"): a randomized multicenter study.

The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1-14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

PURPOSE: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance. PATIENTS AND METHODS: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662. RESULTS: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples. CONCLUSION: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.

A phase Ib study of capecitabine and ziv-aflibercept followed by a phase II single-arm expansion cohort in chemotherapy refractory metastatic colorectal cancer.

BACKGROUND: Patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options. In this phase Ib/II clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then we evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC. METHODS: All patients were required to have a Karnofsky Performance Status > 70% and adequate organ function. The phase Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies. Using a standard 3 + 3 design, we identified the MTD and RPTD for the combination. Fifty patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase II expansion cohort, and were treated at the RPTD. Prior EGFR antibody therapy was required for subjects with RAS wildtype tumors. The primary endpoint for the expansion cohort was progression-free survival (PFS) at two months. Secondary endpoints included objective response rate (ORR) and overall survival (OS). RESULTS: A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion). The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1-14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle. In the expansion cohort, 72% of patients were progression-free at two months (95% confidence interval [CI], 60-84%). Median PFS and OS were 3.9 months (95% CI, 2.3-4.5) and 7.1 months (95% CI: 5.8-10.0), respectively. Among all patients evaluable for toxicity, the most common treatment related adverse events (all grade [%]; grade ≥ 3 [%]) included palmar-plantar erythrodysesthesia (41%; 6%), hypertension (33%; 22%), and mucositis (19%; 5%). RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes. CONCLUSION: The combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability. PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study. TRIAL REGISTRATION: This clinical trial was registered in the www.clinicaltrials.gov system as NCT01661972 on July 31, 2012.

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors.

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study.

BACKGROUND: In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR+/HER2- advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2. PATIENTS AND METHODS: Postmenopausal women with HR+/HER2- ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS. RESULTS: Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia. CONCLUSION: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR+/HER2- ABC.

Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases.

PURPOSE: Brain metastases (BM) are a complication of advanced breast cancer (BC). Histology of melanoma BM offers prognostic value; however, understanding the microenvironment of breast cancer brain metastases (BCBM) is less characterized. This study reports on four histological biomarkers, gliosis, immune infiltrate, hemorrhage, necrosis, and their prognostic significance in BCBM. METHODS: A biobank of 203 human tissues from patients who underwent craniotomy for BCBM was created across four academic institutions. Degree of gliosis, immune infiltrate, hemorrhage, and necrosis were identified and scored via representative H&E stain (0-3+). Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards regression evaluated prognostic value of the biomarkers in the context of standard clinical characteristics. RESULTS: BCBM subtype (available for n = 158) was 36% Her2+, 26% hormone receptor (HR)+/Her2- 38% HR-/Her2- (triple negative, TN). Gliosis was observed in 82% (116/141) of BCBM, with immune infiltrate 44% (90/201), hemorrhage 82% (166/141), and necrosis 87% (176/201). Necrosis was significantly higher in TNBC (p < 0.01). Presence of gliosis, immune infiltrate, and hemorrhage correlated with improved OS (p = 0.03, p = 0.03, p = 0.1), while necrosis correlated with inferior OS (p = 0.01). Improved OS was associated with gliosis in TN (p = 0.02), and immune infiltrate (p = 0.001) and hemorrhage (p = 0.07) in HER2+. In a multivariable model for OS, incorporating these biomarkers with traditional clinical variables improved the model fit (p < 0.001). CONCLUSION: Gliosis confers superior prognosis in TNBC BM; immune infiltrate and hemorrhage correlate with superior prognosis in HER2+ BCBM. Understanding the metastatic microenvironment of BCBM refines prognostic considerations and may unveil novel therapeutic strategies.

TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts. PATIENTS AND METHODS: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m2 twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression. RESULTS: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.

Neratinib in Combination With Trastuzumab for the Treatment of Patients With Advanced HER2-positive Breast Cancer: A Phase I/II Study.

BACKGROUND: Despite the availability of several human epidermal growth factor receptor 2 (HER2)-directed treatments, many HER2-positive (HER2+) breast cancers eventually progress because of primary or acquired resistance. PATIENTS AND METHODS: A 2-part, open-label, multicenter phase I/II study was conducted to determine the recommended dose of neratinib when administered with trastuzumab (part I), and to assess the antitumor activity of this combination in women with locally advanced or metastatic HER2+ breast cancer previously treated with at least 1 prior trastuzumab-based regimen (part II). Patients received oral neratinib (160 or 240 mg/d) once daily plus intravenous trastuzumab 4 mg/kg (loading dose) then 2 mg/kg weekly. Diarrhea prophylaxis was not permitted. The primary endpoint in part II was investigator-assessed 16-week progression-free survival (PFS). RESULTS: Forty-five patients received neratinib plus trastuzumab (part I: neratinib 160 mg/d, n = 4; neratinib 240 mg/d, n = 4; part II: neratinib 240 mg/d, n = 37). In part I, there were no dose-limiting toxicities and the recommended neratinib dose was 240 mg/d. In part II, the 16-week PFS rate was 44.8% (90% confidence interval, 28.8%-59.6%), and the median PFS was 15.9 weeks (95% confidence interval, 15.1-31.3 weeks) in 28 evaluable patients. Three patients had durable clinical benefit lasting 9.4 to 9.7 years. Diarrhea was the most common adverse event (grade 3, n = 7 [15.6%]; grade 4, n = 0). No clinically significant cardiac toxicity was seen. CONCLUSIONS: Neratinib in combination with trastuzumab was well-tolerated and had encouraging antitumor activity in patients with advanced trastuzumab-pretreated HER2+ breast cancer. Durable responses can be achieved in some patients.

Vaccine-Induced Memory CD8+ T Cells Provide Clinical Benefit in HER2 Expressing Breast Cancer: A Mouse to Human Translational Study.

PURPOSE: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). PATIENTS AND METHODS: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. RESULTS: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. CONCLUSIONS: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

Fulvestrant is recommended for patients with hormone receptor-positive (HR+) advanced breast cancer (ABC) who progress after aromatase inhibitor therapy. As most patients in this setting have already developed mechanisms of resistance to endocrine therapy, targeting biological pathways associated with endocrine resistance in combination with fulvestrant may improve outcomes. Therefore, evidence supporting a combinatorial treatment approach in the second-line setting was investigated based on a search of PubMed and ClinicalTrials.gov . Twenty-eight studies of targeted therapies plus fulvestrant as second-line treatment for HR+ ABC were identified, including three and six key randomized trials exploring cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors plus fulvestrant respectively. Additional combinations with fulvestrant included inhibitors of epidermal growth factor receptors, androgen receptor, and the bromodomain and extra-terminal family of proteins. Across the studies reviewed with available data, the addition of targeted therapies to fulvestrant resulted in clinically meaningful improvements in progression-free survival compared with fulvestrant alone. While some challenging toxicities were observed, most adverse events could be effectively managed. Selection of second-line targeted therapy for use with fulvestrant should consider prior treatment as well as the mutation status of the tumor. In conclusion, available data indicate that fulvestrant combined with agents targeting mechanisms of endocrine resistance is a promising approach. The ongoing trials identified in this review will help further inform the selection of combination treatments with fulvestrant for HR+ ABC.

Correction to: Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer.

The article Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer, written by Sarah Sammons, Noah S. Kornblum and Kimberly L. Blackwell, was originally published electronically on the publisher's internet portal (currently SpringerLink).

Endobronchial Ultrasound-guided Transbronchial Needle Aspiration in the Diagnosis of Breast Cancer Thoracic Metastases and Detection of Receptor Discordance.

BACKGROUND: Metastasis of breast cancer to mediastinal lymph nodes is common and biopsy of suspicious lesions can have important diagnostic, prognostic, and therapeutic implications, particularly with respect to tumor receptor status. Our aim was to show that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) can be used for the diagnosis of metastatic breast cancer and demonstrate reliable receptor evaluation that can result in change of therapy. METHODS: A retrospective review of consecutive adult patients undergoing EBUS-TBNA from May 2007 to September 2012 was performed. Data collected for patients with a history of breast cancer included patient demographics, tumor pathology, receptor analysis, imaging, and bronchoscopy or surgical results. RESULTS: Sixty-four patients with a history of breast cancer aged from 31 to 81 years underwent EBUS-TBNA for the evaluation of mediastinal lymphadenopathy of which 16 patients had not been previously treated for their breast cancer with systemic therapy. Eighty suspicious lymph nodes were biopsied measuring 0.8 to 3.1 cm in diameter. Fifty-nine (92%) patients had diagnostic cytology for malignancy or benign lymphoid tissue. Breast malignancy was identified in 33 (52%) patients and 23 (70%) of these had sufficient samples for the evaluation of estrogen, progesterone, and human epidermal growth factor receptor 2 status. Overall 48% of the patients with receptors analyzed had discordance between the primary tumor and metastasis. CONCLUSIONS: EBUS-TBNA is a useful tool for evaluating mediastinal lymphadenopathy in patients with a history of breast cancer and can provide information on the concordance of receptors status between the primary tumor and metastatic sites in the thorax.

Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer.

PURPOSE: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer. METHODS: Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24). RESULTS: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported. CONCLUSIONS: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.

Early Stage HER2-Positive Breast Cancers Not Achieving a pCR From Neoadjuvant Trastuzumab- or Pertuzumab-Based Regimens Have an Immunosuppressive Phenotype.

BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) might predict pathologic complete response (pCR) in patients with HER2-positive (HER2+) breast cancer treated with trastuzumab (H). Docetaxel (T), carboplatin (C), H, and pertuzumab (P) have immune-modulating effects. Pre- and post-treatment immune biomarkers in cancers treated with neoadjuvant TCH with or without P are lacking. In this study we quantified baseline and changes in TILs, cluster of differentiation (CD) 4+, CD8+, FoxP3+, and PD-L1+ cells using immunohistochemistry (IHC) and quantified productive T-cell receptor ß (TCRß) rearrangements and TCRß clonality using next-generation sequencing (NGS) in 30 HER2+ breast cancer tissues treated with neoadjuvant H with or without P regimens. MATERIALS AND METHODS: Thirty pre- and post-neoadjuvant TCH (n = 4) or TCHP (n = 26) breast cancer tissues were identified. TILs were quantified manually using hematoxylin and eosin. CD4, CD8, FoxP3, and PD-L1 were stained using IHC. TCRß was evaluated using NGS. Immune infiltrates were compared between pCR and non-pCR groups using the Wilcoxon rank sum test. RESULTS: A pCR occurred in 15 (n = 15; 50%) cancers (TCH n = 2; TCHP, n = 13). Pretreatment TILs, CD4+, CD8+, FoxP3+, and PD-L1+ cells were not associated with response (P = .42, P = .55, P = .19, P = .66, P = .87, respectively. Pretreatment productive TCRß and TCRß clonality did not predict response, P = .84 and P = .40, respectively). However, post-treatment CD4+ and FoxP3+ cells (T-regulatory cells) were elevated in the non-pCR cohort (P = .042 and P = .082, respectively). CONCLUSION: An increase in regulatory T cells in non-pCR tissues suggests the development of an immunosuppressive phenotype. Further investigation in a larger cohort of samples is warranted to validate these findings.

The Global Need for a Trastuzumab Biosimilar for Patients With HER2-Positive Breast Cancer.

Trastuzumab improves survival outcomes for patients with HER2-positive (HER2+) breast cancer, yet not all such women receive this important therapy. Trastuzumab was approved by the US Food and Drug Administration in 1998 and the European Medicines Agency in 2000 as treatment for HER2+ metastatic breast cancer (MBC). Observational studies between 2000 and 2015 in patients with HER2+ MBC suggest that nearly 12% in the United States, 27% to 54% in Europe, and 27.1% to 49.2% in China did not receive trastuzumab or any other HER2-targeted agent as first- and/or later-line for treatment of metastatic disease. In 2006, both agencies approved trastuzumab as adjuvant therapy for patients with HER2+ early breast cancer (EBC). Observational studies on real-world treatment patterns for HER2+ EBC between 2005 and 2015 suggest that 19.1% to 59.5% of patients across regions of North America, Europe, Australia, New Zealand, and China did not receive (neo)adjuvant trastuzumab. Data suggest that some patient subgroups, including older patients, those with HER2+/hormone receptor-positive disease, and women with small and/or node-negative HER2+ tumors, were less likely to receive anti-HER2 therapy. Barriers to accessing trastuzumab are multifactorial and include issues related to drug funding and high treatment costs for patients that have been reported worldwide. Herein, we review available literature on the use of, and barriers to, treatment with trastuzumab in patients with HER2+ breast cancer. We also discuss how the availability of safe and effective biosimilars might increase access to trastuzumab and allow greater use of anti-HER2 therapy, potentially improving patient outcomes.

Safety Profile of Biosimilar Filgrastim (Zarzio/Zarxio): A Combined Analysis of Phase III Studies.

BACKGROUND: Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim. MATERIALS AND METHODS: Data were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double-blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single-arm, open-label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for <14 days or until the absolute neutrophil count reached 10 × 109/L after the expected nadir. Results were combined for cycles 1-4. RESULTS: A total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim-related. The most frequently reported filgrastim-related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim-related). No patient developed antidrug antibodies during the study. CONCLUSION: Biosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer. IMPLICATIONS FOR PRACTICE: The biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim-sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics.

Leptomeningeal disease: current diagnostic and therapeutic strategies.

Leptomeningeal disease has become increasingly prevalent as novel therapeutic interventions extend the survival of cancer patients. Although a majority of leptomeningeal spread occurs secondary to breast cancer, lung cancer, and melanoma, a wide variety of malignancies have been reported as primary sources. Symptoms on presentation are equally diverse, often involving a combination of neurological deficits with the possibility of obstructive hydrocephalus. Diagnosis is definitively made via cerebrospinal fluid cytology for malignant cells, but neuro-imaging with high quality T1-weighted magnetic resonance imaging can aid diagnosis and localization. While leptomeningeal disease is still a terminal, late-stage complication, a variety of treatment modalities, such as intrathecal chemotherapeutics and radiation therapy, have improved median survival from 4-6 weeks to 3-6 months. Positive prognosticative factors for survival include younger age, high performance scores, and controlled systemic disease. In looking to the future, diagnostics that improve early detection and chemotherapeutics tailored to the primary malignancy will likely be the most significant advances in improving survival.

Association Between Targeted HER-2 Therapy and Breast Reconstruction Outcomes: A Propensity Score-Matched Analysis.

BACKGROUND: Current treatment for HER-2+ breast cancer includes chemotherapy and targeted HER-2 therapy with trastuzumab and/or pertuzumab. Evidence is lacking on the safety of breast reconstructive operations in these patients. We hypothesized that targeted HER-2 therapy was not associated with post-mastectomy reconstructive outcomes. STUDY DESIGN: Women receiving chemotherapy and post-mastectomy reconstruction at Duke University Medical Center from 2006 to 2016 were retrospectively identified. Patients receiving targeted HER-2 therapy with trastuzumab and/or pertuzumab within 6 weeks before breast reconstruction were propensity score-matched 1:1 to patients who did not receive targeted HER-2 therapy, based on the following factors: age, obesity, diabetes, tobacco use, receipt of neoadjuvant chemotherapy, chemotherapy regimen, and radiation therapy. Primary study outcomes included the occurrence of hematoma, seroma, infection, wound breakdown, mastectomy skin flap necrosis, and postoperative flap thrombosis. RESULTS: A total of 481 women were identified, resulting in 107 propensity score-matched pairs. Administration of combined trastuzumab and pertuzumab therapy before breast reconstruction was independently associated with increased risk of postoperative wound breakdown requiring operative intervention for closure, compared with patients not undergoing targeted HER-2 therapy (odds ratio 65.29; 95% CI 1.63 to 2,611.50; p = 0.03). In addition, larger tumor size (2 to 5 cm) was significantly associated with a reduced risk of postoperative wound breakdown, compared with smaller tumors (<2 cm) (odds ratio 0.41; 95% CI 0.19 to 0.87; p = 0.02). Single-agent targeted HER-2 therapy with trastuzumab was not significantly associated with reconstructive complications. CONCLUSIONS: Our study suggests that trastuzumab therapy in conjunction with breast reconstructive operation is not associated with reconstructive complications, and breast reconstruction does not need to be delayed due to the administration of trastuzumab. Future studies are needed to evaluate the impact of pertuzumab on surgical outcomes.