Publications by authors named "Cynthia X Ma"

91 Publications

The phase II MutHER study of neratinib alone and in combination with fulvestrant in HER2 mutated, non-amplified metastatic breast cancer.

Clin Cancer Res 2022 Jan 19. Epub 2022 Jan 19.

Medicine, Division of Oncology, Washington University in St. Louis School of Medicine.

Purpose: HER2 mutations (HER2) induce endocrine resistance in estrogen receptor positive (ER+) breast cancer.

Experimental Design: In this single arm multi-cohort phase II trial, we evaluated the efficacy of neratinib plus fulvestrant in patients with ER+/HER2, HER2-non-amplified metastatic breast cancer (MBC) in the fulvestrant-treated (n=24) or fulvestrant-naïve cohort (n=11). Patients with ER-negative/HER2 MBC received neratinib monotherapy in an exploratory ER- cohort (n=5).

Results: The clinical benefit rate (CBR: 95% CI) was 38% (18-62%), 30% (7-65%), and 25% (1-81%) in the fulvestrant-treated, fulvestrant-naïve, and ER- cohort, respectively. Adding trastuzumab at progression in 5 patients resulted in 3 partial responses and 1 stable disease {greater than or equal to}24 weeks. CBR appeared positively associated with lobular histology and negatively associated with HER2 L755 alterations. Acquired HER2 were detected in 5 of 23 patients at progression.

Conclusion: Neratinib and fulvestrant is active for ER+/HER2 MBC. Our data supports further evaluation of dual HER2 blockade for the treatment of HER2 MBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-3418DOI Listing
January 2022

Effective Treatment of Established Bone Metastases Can Be Achieved by Combinatorial Osteoclast Blockade and Depletion of Granulocytic Subsets.

Cancer Immunol Res 2021 12 22;9(12):1400-1412. Epub 2021 Sep 22.

Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri.

Osteoclast (OC) blockade has been successful in reducing tumor growth in bone in preclinical settings, but antiresorptive drugs, such as zoledronic acid (ZA), fail to improve the overall survival rate of patients with bone metastasis despite ameliorating skeletal complications. To address this unmet clinical need, we interrogated what other cells modulated tumor growth in bone in addition to OCs. Because myeloid-derived suppressor cells (MDSC)-heterogeneous populations expressing CD11b, Ly6C, and Ly6G markers-originate in the bone marrow and promote tumor progression, we hypothesized that their accumulation hinders ZA antitumor effects. By using a murine model of bone metastasis insensitive to OC blockade, we assessed the antitumor effect of MDSC depletion using anti-Gr1 in mice bearing skeletal lung [Lewis lung carcinoma (LLC)], melanoma (B16-F10), and mammary (4T1) tumors. Differently from soft tissue tumors, anti-Gr1 did not reduce bone metastases and led to the paradoxical accumulation of bone marrow-resident CD11bLy6CLy6G cells that differentiated into OCs when cultured Anti-Gr1-mediated depletion of Ly6G granulocytic MDSCs combined with ZA-induced OC blockade reduced growth of established skeletal metastases compared with each agent alone. CD15 granulocytic populations were increased in patients with breast cancer with progressive bone disease after antiresorptive treatment compared with those with stable bone disease. We provide evidence that antiresorptive therapies fail to reduce bone metastases in the presence of elevated granulocytic populations and that effective treatment of established skeletal metastases requires combinatorial depletion of granulocytes and OC blockade.
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http://dx.doi.org/10.1158/2326-6066.CIR-21-0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642282PMC
December 2021

Breast Cancer, Mutations, and Overcoming Drug Resistance.

N Engl J Med 2021 Sep;385(13):1241-1243

From the Division of Oncology, Department of Medicine, and the Siteman Cancer Center, Washington University School of Medicine, St. Louis.

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http://dx.doi.org/10.1056/NEJMcibr2110552DOI Listing
September 2021

Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment.

Nat Commun 2021 08 24;12(1):5086. Epub 2021 Aug 24.

Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA.

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs' recapitulation of human tumors.
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http://dx.doi.org/10.1038/s41467-021-25177-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384880PMC
August 2021

Intermittent fasting in the prevention and treatment of cancer.

CA Cancer J Clin 2021 11 12;71(6):527-546. Epub 2021 Aug 12.

School of Medicine, Division of Medical Oncology, Washington University in St Louis, St Louis, Missouri.

Chronic caloric restriction (CR) has powerful anticarcinogenic actions in both preclinical and clinical studies but may be difficult to sustain. As an alternative to CR, there has been growing interest in intermittent fasting (IF) in both the scientific and lay community as a result of promising study results, mainly in experimental animal models. According to a survey by the International Food Information Council Foundation, IF has become the most popular diet in the last year, and patients with cancer are seeking advice from oncologists about its beneficial effects for cancer prevention and treatment. However, as discussed in this review, results from IF studies in rodents are controversial and suggest potential detrimental effects in certain oncologic conditions. The effects of IF on human cancer incidence and prognosis remain unknown because of a lack of high-quality randomized clinical trials. Preliminary studies suggest that prolonged fasting in some patients who have cancer is safe and potentially capable of decreasing chemotherapy-related toxicity and tumor growth. However, because additional trials are needed to elucidate the risks and benefits of fasting for patients with cancer, the authors would not currently recommend patients undergoing active cancer treatment partake in IF outside the context of a clinical trial. IF may be considered in adults seeking cancer-prevention benefits through means of weight management, but whether IF itself affects cancer-related metabolic and molecular pathways remains unanswered.
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http://dx.doi.org/10.3322/caac.21694DOI Listing
November 2021

Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.

Breast Cancer Res Treat 2021 Aug 26;189(1):187-202. Epub 2021 Jun 26.

Lester & Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Purpose: Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR.

Experimental Design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles.

Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR.

Conclusion: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR.

Trial Registration: Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.
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http://dx.doi.org/10.1007/s10549-021-06307-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443324PMC
August 2021

Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience.

J Natl Compr Canc Netw 2021 Mar 24:1-8. Epub 2021 Mar 24.

1Massachusetts General Hospital Cancer Center, and.

Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor-positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i.

Patients And Methods: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers.

Results: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib.

Conclusions: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.
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http://dx.doi.org/10.6004/jnccn.2020.7662DOI Listing
March 2021

Cisplatin +/- rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer.

NPJ Breast Cancer 2021 Mar 22;7(1):29. Epub 2021 Mar 22.

Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.

Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5 cm) with 1 (0-38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82-4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.
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http://dx.doi.org/10.1038/s41523-021-00240-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985189PMC
March 2021

RNA Based Approaches to Profile Oncogenic Pathways From Low Quantity Samples to Drive Precision Oncology Strategies.

Front Genet 2020 5;11:598118. Epub 2021 Feb 5.

University of California, San Diego, La Jolla, CA, United States.

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling pathways simultaneously and quantitatively with high resolution in tissue samples and circulating tumor cells, specifically with very small specimen quantities. The approach uses mRNA levels of a pathway's direct target genes, selected based on literature for multiple proof points, and used as evidence that a pathway is functionally activated. Using these validated target genes, a Bayesian network model has been built and calibrated on mRNA measurements of samples with known pathway status, which is used next to calculate a pathway activity score on individual test samples. Translation to RT-qPCR assays enables broad clinical diagnostic applications, including small analytes. A large number of cancer samples have been analyzed across a variety of cancer histologies and benchmarked across normal controls. Assays have been used to characterize cell types in the cancer cell microenvironment, including immune cells in which activated and immunotolerant states can be distinguished. Results support the expectation that the assays provide information on cancer driving signaling pathways which is difficult to derive from next generation DNA sequencing analysis. Current clinical oncology applications have been complementary to genomic mutation analysis to improve precision medicine: (1) prediction of response and resistance to various therapies, especially targeted therapy and immunotherapy; (2) assessment and monitoring of therapy efficacy; (3) prediction of invasive cancer cell behavior and prognosis; (4) measurement of circulating tumor cells. Preclinical oncology applications lie in a better understanding of cancer behavior across cancer types, and in development of a pathophysiology-based cancer classification for development of novel therapies and precision medicine.
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http://dx.doi.org/10.3389/fgene.2020.598118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893109PMC
February 2021

Cancer-associated exportin-6 upregulation inhibits the transcriptionally repressive and anticancer effects of nuclear profilin-1.

Cell Rep 2021 02;34(7):108749

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Aberrant expression of nuclear transporters and deregulated subcellular localization of their cargo proteins are emerging as drivers and therapeutic targets of cancer. Here, we present evidence that the nuclear exporter exportin-6 and its cargo profilin-1 constitute a functionally important and frequently deregulated axis in cancer. Exportin-6 upregulation occurs in numerous cancer types and is associated with poor patient survival. Reducing exportin-6 level in breast cancer cells triggers antitumor effects by accumulating nuclear profilin-1. Mechanistically, nuclear profilin-1 interacts with eleven-nineteen-leukemia protein (ENL) within the super elongation complex (SEC) and inhibits the ability of the SEC to drive transcription of numerous pro-cancer genes including MYC. XPO6 and MYC are positively correlated across diverse cancer types including breast cancer. Therapeutically, exportin-6 loss sensitizes breast cancer cells to the bromodomain and extra-terminal (BET) inhibitor JQ1. Thus, exportin-6 upregulation is a previously unrecognized cancer driver event by spatially inhibiting nuclear profilin-1 as a tumor suppressor.
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http://dx.doi.org/10.1016/j.celrep.2021.108749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006859PMC
February 2021

Association of PET-based estradiol-challenge test for breast cancer progesterone receptors with response to endocrine therapy.

Nat Commun 2021 02 2;12(1):733. Epub 2021 Feb 2.

Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

Estrogen receptor (ER) testing of breast cancer imperfectly predicts response to endocrine therapy (ET). We hypothesize that a brief estradiol challenge will increase tumor progesterone receptor (PgR) levels only in tumors with functional ER. In this prospective, phase 2, single-center, single-arm trial (NCT02455453), we report the association of response to ET with change in tumor uptake of the progestin analog, 21-[F]fluorofuranylnorprogesterone (FFNP), before and after a one-day estradiol challenge. In 43 postmenopausal women with advanced ER+ breast cancer, we show a post-challenge increase in tumor FFNP uptake only in 28 subjects with clinical benefit from ET (responders), but not in 15 without clinical benefit (nonresponders) (p < 0.0001), indicating 100% sensitivity and specificity. We further show significantly longer survival (p < 0.0001) in the responding subjects. Our results demonstrate that change in tumor FFNP uptake after estradiol challenge is highly predictive of response to ET in women with ER+ breast cancer.
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http://dx.doi.org/10.1038/s41467-020-20814-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854611PMC
February 2021

Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models.

Cancers (Basel) 2020 Dec 21;12(12). Epub 2020 Dec 21.

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.
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http://dx.doi.org/10.3390/cancers12123857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765949PMC
December 2020

Clinical Challenges in the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: A Literature Review.

Adv Ther 2021 01 15;38(1):109-136. Epub 2020 Nov 15.

Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Endocrine therapy (ET) is integral to the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Aromatase inhibitors (AIs; e.g., anastrozole, letrozole, exemestane), selective estrogen receptor modulators (e.g., tamoxifen), and the selective estrogen receptor degrader, fulvestrant, inhibit tumor cell proliferation by targeting ER signaling. However, the efficacy of ET could be limited by intrinsic and acquired resistance mechanisms, which has prompted the development of targeted agents and combination strategies. In recent years, the treatment landscape for HR+, HER2- MBC has evolved rapidly. AIs, historically the first-line treatment for postmenopausal patients with HR+, HER2- MBC, have been challenged by more effective ET, such as fulvestrant alone or in combination with an AI, and the cyclin-dependent kinase (CDK)4/6 inhibitors, which have increasingly become the new standard of care. For endocrine-resistant disease (≥ second-line), clinical trials demonstrated that the mammalian target of rapamycin inhibitor, everolimus, enhanced the efficacy of exemestane or fulvestrant after progression on an AI. CDK4/6 inhibitors in combination with fulvestrant have demonstrated superior progression-free survival and overall survival versus fulvestrant alone. Recently, the combination of fulvestrant with alpelisib in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutated HR+, HER2- MBC following progression on or after ET was approved, based on the SOLAR-1 study. However, the optimal sequencing of treatments is unknown, especially following disease progression on a CDK4/6 inhibitor. This review aims to provide practical guidance for the management of HR+, HER2- MBC based on available data and the utility of genomic biomarkers, including germline breast cancer genes 1 and 2 (BRCA1/2) mutations, and somatic estrogen receptor alpha gene (ESR1), HER2, and PIK3CA mutations.
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http://dx.doi.org/10.1007/s12325-020-01552-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854469PMC
January 2021

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with -Mutant Cancers.

Clin Cancer Res 2021 01 4;27(2):447-459. Epub 2020 Nov 4.

Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, New York.

Purpose: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with -mutant cancers with the isoform-specific PI3K inhibitor taselisib.

Patients And Methods: Patients were enrolled on the basis of local mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.

Results: A total of 166 patients with -mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront ( and ) and postprogression through reactivation of the PI3K pathway (, and ). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.

Conclusions: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target -mutant tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2657DOI Listing
January 2021

Identifying Activating Mutations in HER2-Negative Breast Cancer: Clinical Impact of Institute-Wide Genomic Testing and Enrollment in Matched Therapy Trials.

JCO Precis Oncol 2019 15;3. Epub 2019 Nov 15.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: The yield of comprehensive genomic profiling in recruiting patients to molecular-based trials designed for small subgroups has not been fully evaluated. We evaluated the likelihood of enrollment in a clinical trial that required the identification of a specific genomic change based on our institute-wide genomic tumor profiling.

Patients And Methods: Using genomic profiling from archived tissue samples derived from patients with metastatic breast cancer treated between 2011 and 2017, we assessed the impact of systematic genomic characterization on enrollment in an ongoing phase II trial (ClinicalTrials.gov identifier: NCT01670877). Our primary aim was to describe the proportion of patients with a qualifying mutation identified by our institutional genomic panel (OncoMap or OncoPanel) who enrolled in the trial. Secondary objectives included median time from testing result to trial registration, description of the spectrum of mutations, and survival. Associations were calculated using Fisher's exact test.

Results: We identified a total of 1,045 patients with metastatic breast cancer without amplification who had available genomic testing results. Of these, 42 patients were found to have mutation and 19 patients (1.8%) were eligible for the trial on the basis of the presence of an activating mutation, 18 of which were identified by OncoPanel testing. Fifty-eight percent of potentially eligible patients were approached, and 33.3% of eligible patients enrolled in the trial guided exclusively by OncoPanel testing.

Conclusion: More than one half of eligible patients were approached for trial participation and, significantly, one third of those were enrolled in NCT01670877. Our data illustrate the ability to enroll patients in trials of rare subsets in routine clinical practice and highlight the need for these broadly based approaches to effectively support the success of these studies.
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http://dx.doi.org/10.1200/PO.19.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446367PMC
November 2019

Evidence-based guidelines for managing patients with primary ER+ HER2- breast cancer deferred from surgery due to the COVID-19 pandemic.

NPJ Breast Cancer 2020 8;6:21. Epub 2020 Jun 8.

West German Study Group, Mönchengladbach, Germany.

Many patients with ER+ HER2- primary breast cancer are being deferred from surgery to neoadjuvant endocrine therapy (NeoET) during the COVID-19 pandemic. We have collated data from multiple international trials of presurgical endocrine therapy in order to provide guidance on the identification of patients who may have insufficiently endocrine-sensitive tumors and should be prioritised for early surgery or neoadjuvant chemotherapy rather than NeoET during or in the aftermath of the COVID-19 pandemic for safety or when surgical activity needs to be prioritized. For postmenopausal patients, our data provide strong support for the use of ER and PgR status at diagnosis for triaging of patients into three groups in which (taking into account clinical factors): (i) NeoET is likely to be inappropriate (Allred ER <6 or ER 6 and PgR <6) (ii) a biopsy for Ki67 analysis (on-treatment Ki67) could be considered after 2-4 weeks of NeoET (a: ER 7 or 8 and PgR <6 or b: ER 6 or 7 and PgR ≥6) or (iii) NeoET is an acceptable course of action (ER 8 and PgR ≥6). Cut-offs for percentage of cells positive are also given. For group (ii), a high early on-treatment level of Ki67 (>10%) indicates a higher priority for early surgery. Too few data were available for premenopausal patients to provide a similar treatment algorithm. These guidelines should be helpful for managing patients with early ER+ HER2- breast cancer during and in the aftermath of the COVID-19 crisis.
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http://dx.doi.org/10.1038/s41523-020-0168-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280290PMC
June 2020

Sequencing Endocrine Therapy for Metastatic Breast Cancer: What Do We Do After Disease Progression on a CDK4/6 Inhibitor?

Curr Oncol Rep 2020 05 16;22(6):57. Epub 2020 May 16.

Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Ave, Campus Box 8076, St. Louis, MO, 63110, USA.

Purpose Of Review: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment landscape for patients with hormone receptor-positive (HR+) and HER2-negative (HER2-) metastatic breast cancer (MBC). However, optimal therapy after CDK4/6 inhibitors is unknown. This review provides an update on recent understanding of potential resistance mechanisms to CDK4/6 inhibitors and therapeutic strategies.

Recent Findings: CDK4/6 inhibitors are broadly effective for HR+/HER2- MBC. However, intrinsic and acquired resistance is inevitable. Although there are no established clinical predictors of response aside from ER positivity, several cell cycle-specific and non-specific mechanisms have emerged as potential resistance biomarkers and therapeutic targets in recent studies. Examples include loss of function mutations in RB1 or FAT1, overexpression or amplification of CDK6 and CCNE1, alterations of FGFR, and PI3K/mTOR-mediated CDK2 activation. Biomarker studies and clinical trials targeting CDK4/6 inhibitor resistance are critical to improve treatments for HR+/HER2- MBC.
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http://dx.doi.org/10.1007/s11912-020-00917-8DOI Listing
May 2020

Predictors of Distant Metastases in Triple-Negative Breast Cancer Without Pathologic Complete Response After Neoadjuvant Chemotherapy.

J Natl Compr Canc Netw 2020 03;18(3):288-296

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) predicts decreased distant metastasis. However, most patients do not experience pCR, and other risk factors for distant metastasis after NAC are poorly characterized. This study investigated factors predictive of distant metastasis in TNBC without pCR after NAC.

Methods: Women with TNBC treated with NAC, surgery, and radiation therapy in 2000 through 2013 were reviewed. Freedom from distant metastasis (FFDM) was compared between patients with and without pCR using the Kaplan-Meier method. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of distant metastasis.

Results: We identified 153 patients with median follow-up of 4.0 years (range, 0.5-14.0 years). After NAC, 108 had residual disease (pCR, 29%). Five-year FFDM was 98% and 55% in patients with and without pCR, respectively (P<.001). Factors independently predicting FFDM in patients without pCR were pathologic nodal positivity (hazard ratio, 3.08; 95% CI, 1.54-6.14; P=.001) and lymphovascular space invasion (hazard ratio, 1.91; 95% CI, 1.07-3.43; P=.030). Patients with a greater number of factors had worse FFDM; 5-year FFDM was 76.5% for patients with no factors (n=38) versus 54.9% and 27.5% for patients with 1 (n=44) and 2 factors (n=26), respectively (P<.001).

Conclusions: Lack of pCR after NAC resulted in worse overall survival and FFDM, despite trimodality therapy. In patients with residual disease after NAC, pathologic lymph node positivity and lymphovascular space invasion predicted worse FFDM.
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http://dx.doi.org/10.6004/jnccn.2019.7366DOI Listing
March 2020

PI3K Inhibitors in Breast Cancer Therapy.

Curr Oncol Rep 2019 12 11;21(12):110. Epub 2019 Dec 11.

Division of Oncology, Department of Medicine, Siteman Cancer Center, School of Medicine, Washington University, 660 South Euclid Ave, St. Louis, MO, 63110, USA.

Purpose Of Review: The phosphatidylinositol 3-kinase (PI3K) pathway is the most common aberrantly activated pathway in breast cancer, making it an attractive therapeutic target. In this review, we will discuss the rationale for targeting PI3K/AKT signaling and the development of PI3K/AKT inhibitors in breast cancer.

Recent Findings: Although the initial clinical trials with pan-PI3K inhibitors were challenged by high toxicities and modest antitumor effect, there has been continued effort to develop agents more precisely targeting PI3K isoforms to improve therapeutic index. Alpelisib in combination with fulvestrant is now available in the clinic for postmenopausal women with advanced or metastatic hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated breast cancer. In addition, promising data has been observed in randomized phase II trials of AKT inhibitors in combination with fulvestrant or paclitaxel in metastatic HR-positive, HER2-negative disease and triple negative breast cancer (TNBC), respectively. The high frequency of genetic alterations in the PI3K pathway has provided the rationale for development of inhibitors targeting PI3K/AKT. Despite initial disappointment with several randomized trials of pan-PI3K inhibitors in HR-positive breast cancer, there has been continued effort to more precisely target PI3K isoforms, which has led to clinical benefit for patients with advanced breast cancer.
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http://dx.doi.org/10.1007/s11912-019-0846-7DOI Listing
December 2019

PI3K inhibition enhances the anti-tumor effect of eribulin in triple negative breast cancer.

Oncotarget 2019 Jun 4;10(38):3667-3680. Epub 2019 Jun 4.

Section of Medical Oncology, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) is commonly observed in triple negative breast cancer (TNBC), leading to activation of the phosphoinositide 3-kinase (PI3K) signaling to promote tumor cell growth and chemotherapy resistance. In this study, we investigated whether adding a pan-PI3K inhibitor could improve the cytotoxic effect of eribulin, a non-taxane microtubule inhibitor, in TNBC patient-derived xenograft models (PDX) with loss of PTEN, and the underlying molecular mechanisms. Three TNBC-PDX models (WHIM6, WHIM12 and WHIM21), all with loss of PTEN expression, were tested for their response to BKM120 and eribulin, alone or in combination . In addition, the effect of drug treatment on cell proliferation and cell cycle progression were also performed using a panel of TNBC cell lines, including 2 derived from PDX models. The combination of eribulin and BKM120 led to additive or synergistic anti-tumor effect in 2 of the 3 PDX models, accompanied by an enhanced mitotic arrest and apoptosis in sensitive PDX models. In addition, the combination was synergistic in reducing mammosphere formation, and markers for epithelial-mesenchymal transition (EMT). In conclusion, PI3K inhibition induces synergistic anti-tumor effect when combined with eribulin, by enhancing mitotic arrest and apoptosis, as well as, reducing the cancer stem cell population. This study provides a preclinical rationale to investigate the therapeutic potential for the combination of PI3K inhibition and eribulin in the difficult to treat TNBC. Further studies are needed to identify the biomarkers of response for target patient selection.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557212PMC
June 2019

Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer.

J Natl Compr Canc Netw 2019 02;17(2):141-147

aWashington University School of Medicine, and.

Cyclin-dependent kinase (CDK) 4/6 inhibitors are now the standard of care for hormone receptor-positive (HR+), HER2-negative (HER-) metastatic breast cancer (MBC). However, guidelines are lacking regarding their optimal sequencing with other available agents. This study examines physician practice patterns and treatment outcomes of palbociclib and subsequent therapies in a real-world setting. A retrospective chart review was conducted for consecutive patients with MBC who received palbociclib between February 2015 and August 2017 at the Alvin J. Siteman Cancer Center. Kaplan-Meier method was used to generate time-to-event curves and estimate median progression-free survival (mPFS). Log-rank test was used to compare differences. A total of 200 patients, with a median age of 59.4 years and a follow-up of 19.5 months, were included. Palbociclib was most frequently combined with letrozole (73.5%), followed by fulvestrant (25%), anastrozole (1%), and tamoxifen (0.5%). Most patients received palbociclib in the endocrine-resistant setting (n=42, n=50, and n=108 in the first-, second-, and subsequent-line settings, respectively), and the fraction of patients receiving palbociclib as first- or second-line therapy increased in recent months (=.0428). mPFS was 20.7, 12.8, and 4.0 months with palbociclib administered in the first-, second-, and subsequent-line settings, respectively (<.0001). Incidences of grade 3/4 neutropenia (41.5%) and dose reductions (29%) were comparable to reports in the literature. Among patients whose disease progressed on palbociclib (n=104), the most frequent next-line treatment was capecitabine (n=21), followed by eribulin (n=16), nab-paclitaxel (n=15), and exemestane + everolimus (n=12). mPFS with hormone therapy alone or in combination with targeted agents (n=32) after first-, second-, and subsequent-line palbociclib was 17.0, 9.3, and 4.2 months, respectively (=.04). mPFS with chemotherapy (n=70) was not reached, 4.7, and 4.1 months after first-, second-, and subsequent-line palbociclib, respectively (=.56). Palbociclib is effective for HR+/HER2- MBC in real-world practice. Hormone therapy alone or in combination with targeted agents remains an effective option after palbociclib progression.
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http://dx.doi.org/10.6004/jnccn.2018.7094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752198PMC
February 2019

Neutrophil-to-lymphocyte ratio as a predictor of survival in patients with triple-negative breast cancer.

Breast Cancer Res Treat 2019 Apr 2;174(2):443-452. Epub 2019 Jan 2.

Washington University School of Medicine, St. Louis, MO, 63110, USA.

Purpose: Peripheral blood lymphopenia and elevated neutrophil-to-lymphocyte ratio (NLR) have been associated with poor outcomes in various malignancies. However, existing literature has largely focused on baseline parameters. The aim of this study is to assess the impact of radiation therapy (RT) and chemotherapy on absolute lymphocyte counts (ALC) and NLR in relation to survival outcomes in patients with triple-negative breast cancer (TNBC).

Methods: A retrospective analysis was performed on 126 patients with TNBC treated at Washington University between 2005 and 2010. Cox proportional hazard model with time-varying covariates was applied to estimate the effect of time-varying ALC and NLR separately on overall survival (OS) and disease-free survival (DFS).

Results: All patients received RT and 112 patients received either neoadjuvant chemotherapy or adjuvant chemotherapy, or both. Patients deceased had lower ALC and higher NLR compared to patients alive throughout the treatment course, even 1 year after treatment completion (ALC, 1 vs. 1.3, P = 0.03 and NLR, 3.9 vs. 2.6, P = 0.03). High ALC was associated with superior OS on both continuous and binary scales (cutoff of 1 K/ul) (HR 0.14; 95% CI 0.05-0.34; P < 0.001 and HR 0.28; 95% CI 0.13-0.61; P = 0.01, respectively). Additionally, high NLR was weakly associated with inferior OS on continuous scales (HR 1.1; 95% CI 1.06-1.15; P < 0.001).

Conclusions: Post-treatment lymphopenia and NLR elevation can persist until 1 year after treatment completion. Both portend shorter survival for patients with TNBC. Our data support the use of ALC and NLR to identify high risk patients who may benefit from clinical trials rather than standard of care therapy.
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http://dx.doi.org/10.1007/s10549-018-05106-7DOI Listing
April 2019

Acquired HER2 mutations in ER metastatic breast cancer confer resistance to estrogen receptor-directed therapies.

Nat Genet 2019 02 10;51(2):207-216. Epub 2018 Dec 10.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.

Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25-30% of people treated with aromatase inhibitors, knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as-in contrast to ER mutations-resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib.
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http://dx.doi.org/10.1038/s41588-018-0287-5DOI Listing
February 2019

Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER breast cancer.

FASEB J 2019 02 30;33(2):1644-1657. Epub 2018 Aug 30.

Department of Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.

Despite the success of approved systemic therapies for estrogen receptor α (ER)-positive breast cancer, drug resistance remains common. We hypothesized that secreted factors from the human tumor microenvironment could modulate drug resistance. We previously screened a library of 297 recombinant-secreted microenvironmental proteins for the ability to confer resistance to the anti-estrogen fulvestrant in 2 ER breast cancer cell lines. Herein, we considered whether factors that enhanced drug sensitivity could be repurposed as therapeutics and provide leads for drug development. Screening data revealed bone morphogenic protein (BMP)4 as a factor that inhibited cell growth and synergized with approved anti-estrogens and cyclin-dependent kinase 4/6 inhibitors (CDK4/6). BMP4-mediated growth inhibition was dependent on type I receptor activin receptor-like kinase (ALK)3-dependent phosphorylation (P) of mothers against decapentaplegic homolog (SMAD/P-SMAD)1 and 5, which could be reversed by BMP receptor inhibitors and ALK3 knockdown. The primary effect of BMP4 on cell fate was cell-cycle arrest, in which RNA sequencing, immunoblot analysis, and RNA interference revealed to be dependent on p21 upregulation. BMP4 also enhanced sensitivity to approved inhibitors of mammalian target of rapamycin complex 1 and CDK4/6 via ALK3-mediated P-SMAD1/5 and p21 upregulation in anti-estrogen-resistant cells. Patients bearing primary ER breast tumors, exhibiting a transcriptomic signature of BMP4 signaling, had improved disease outcome following adjuvant treatment with anti-estrogen therapy, independently of age, tumor grade, and tumor stage. Furthermore, a transcriptomic signature of BMP4 signaling was predictive of an improved biologic response to the CDK4/6 palbociclib, in combination with an aromatase inhibitor in primary tumors. These findings highlight BMP4 and its downstream pathway activation as a therapeutic opportunity in ER breast cancer.-Shee, K., Jiang, A., Varn, F. S., Liu, S., Traphagen, N. A., Owens, P., Ma, C. X., Hoog, J., Cheng, C., Golub, T. R., Straussman, R., Miller, T. W. Cytokine sensitivity screening highlights BMP4 pathway signaling as a therapeutic opportunity in ER breast cancer.
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http://dx.doi.org/10.1096/fj.201801241RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338642PMC
February 2019

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

Cell Rep 2018 08;24(6):1434-1444.e7

Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.
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http://dx.doi.org/10.1016/j.celrep.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171747PMC
August 2018

Male Breast Cancer: An Updated Surveillance, Epidemiology, and End Results Data Analysis.

Clin Breast Cancer 2018 10 27;18(5):e997-e1002. Epub 2018 Jun 27.

Washington University Brown School of Public Health, St. Louis, MO; Section of Medical Oncology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO. Electronic address:

Background: Male breast cancer is rare and understudied compared with female breast cancer. A current comparison with female breast cancer could assist in bridging this gap. Although conflicting data have been reported on male and female survival outcomes, data from 1973 through 2005 in the Surveillance, Epidemiology, and End Results (SEER) program have demonstrated that the improvement in breast cancer survival in men has fallen behind that of women. As treatment for breast cancer has improved significantly, an updated analysis using a contemporary population is necessary.

Materials And Methods: An analysis of SEER data from patients with a diagnosis of primary breast cancer from 2005 to 2010 were included. A Cox regression model was used to examine the association between sex and breast cancer mortality after controlling for prognostic factors, including age, race, marital status, disease stage, estrogen and progesterone receptor status, lymph node involvement, tumor grade, surgery, and geography. Subgroup analyses were performed by race and stage.

Results: We included a total of 289,673 breast cancer cases (2054 men) with a diagnosis from 2005 to 2010. The 5-year survival rate for male patients was lower than that for female patients (82.8% vs. 88.5%). After controlling for other factors, the risk of death in men was 43% greater than that in women during the follow-up period (hazard ratio, 1.43; 95% confidence interval, 1.26-1.61). Similar results were noted in the race and stage subgroup analyses.

Conclusion: In recent years, male breast cancer patients have had worse survival outcomes compared with those of female patients.
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http://dx.doi.org/10.1016/j.clbc.2018.06.013DOI Listing
October 2018

A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation.

Breast Cancer Res Treat 2018 Aug 19;170(3):547-557. Epub 2018 Apr 19.

University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, USA.

Purpose: The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1).

Methods: Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS).

Results: Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran-Mantel-Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar-plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine.

Conclusions: The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.
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http://dx.doi.org/10.1007/s10549-018-4770-6DOI Listing
August 2018

Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers.

Cancer Res 2018 05 22;78(10):2732-2746. Epub 2018 Feb 22.

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Activation of PI3K signaling is frequently observed in triple-negative breast cancer (TNBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib A complex in/del frameshift in decreased sensitivity to buparlisib via NEK9/MAP2K4-dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy. Integrative phosphoproteogenomic analysis is used to determine intrinsic resistance mechanisms of triple-negative breast tumors to PI3K inhibition. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955814PMC
May 2018

Evaluation of [Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer.

Breast Cancer Res Treat 2018 Jun 13;169(3):523-530. Epub 2018 Feb 13.

Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

Purpose: To evaluate whether tumor uptake of [Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer.

Methods: Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 ± 2 days following [Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUV), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [Zr]trastuzumab uptake was evaluated.

Results: On a per-patient basis, [Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2-positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUV was not significantly different in patients with HER2-positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUV was significantly higher in HER2-positive compared to HER2-negative patients (p = 0.003). A cutoff SUV of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2-positive from HER2-negative lesions. There was intrapatient heterogeneity of [Zr]trastuzumab uptake in 20% of patients with multiple lesions.

Conclusions: [Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.
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http://dx.doi.org/10.1007/s10549-018-4696-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955803PMC
June 2018
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