Publications by authors named "Mothaffar F Rimawi"

48 Publications

Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer.

Clin Cancer Res 2021 Feb 3. Epub 2021 Feb 3.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Purpose: Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER)/HER2 breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.

Experimental Design: Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.

Results: Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER/HER2 tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.

Conclusions: Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4191DOI Listing
February 2021

HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis.

Cancer Treat Rev 2020 Mar 17;84:101965. Epub 2020 Jan 17.

Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain; SOLTI Breast Cancer Research Group, Barcelona, Spain; Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. Electronic address:

Background: HER2-positive (HER2+) breast cancer (BC) comprises all the four PAM50 molecular subtypes. Among these, the HER2-Enriched (HER2-E) appear to be associated with higher pathological complete response (pCR) rates following anti-HER2-based regimens. Here, we present a meta-analysis to validate the association of the HER2-E subtype with pCR following anti-HER2-based neoadjuvant treatments with or without chemotherapy (CT).

Methods: A systematic literature search was performed in February 2019. The primary objective was to compare the association between HER2-E subtype (versus others) and pCR. Selected secondary objectives were to compare the association between 1) HER2-E subtype and pCR in CT-free studies, 2) HER2-E subtype within hormone receptor (HR)-negative and HR+ disease and 3) HR-negative disease (versus HR+) and pCR in all patients and within HER2-E subtype. A random-effect model was applied. The Higgins' I was used to quantify heterogeneity.

Results: Sixteen studies were included, 5 of which tested CT-free regimens. HER2-E subtype was significantly associated with pCR in all patients (odds ratio [OR] = 3.50, p < 0.001, I = 33%), in HR+ (OR = 3.61, p < 0.001, I = 1%) and HR-negative tumors (OR = 2.28, p = 0.01, I = 47%). In CT-free studies, HER2-E subtype was associated with pCR in all patients (OR = 5.52, p < 0.001, I = 0%) and in HR + disease (OR = 4.08, p = 0.001, I = 0%). HR-negative status was significantly associated with pCR compared to HR + status in all patients (OR = 2.41, p < 0.001, I = 30%) and within the HER2-E subtype (OR = 1.76, p < 0.001, I = 0%).

Conclusions: The HER2-E biomarker identifies patients with a higher likelihood of achieving a pCR following neoadjuvant anti-HER2-based therapy beyond HR status and CT use. Future trial designs to escalate or de-escalate systemic therapy in HER2+ disease should consider this genomic biomarker.
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http://dx.doi.org/10.1016/j.ctrv.2020.101965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230134PMC
March 2020

Microscaled proteogenomic methods for precision oncology.

Nat Commun 2020 Jan 27;11(1):532. Epub 2020 Jan 27.

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

Cancer proteogenomics promises new insights into cancer biology and treatment efficacy by integrating genomics, transcriptomics and protein profiling including modifications by mass spectrometry (MS). A critical limitation is sample input requirements that exceed many sources of clinically important material. Here we report a proteogenomics approach for core biopsies using tissue-sparing specimen processing and microscaled proteomics. As a demonstration, we analyze core needle biopsies from ERBB2 positive breast cancers before and 48-72 h after initiating neoadjuvant trastuzumab-based chemotherapy. We show greater suppression of ERBB2 protein and both ERBB2 and mTOR target phosphosite levels in cases associated with pathological complete response, and identify potential causes of treatment resistance including the absence of ERBB2 amplification, insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification, and candidate resistance mechanisms including androgen receptor signaling, mucin overexpression and an inactive immune microenvironment. The clinical utility and discovery potential of proteogenomics at biopsy-scale warrants further investigation.
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http://dx.doi.org/10.1038/s41467-020-14381-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985126PMC
January 2020

Towards personalized treatment for early stage HER2-positive breast cancer.

Nat Rev Clin Oncol 2020 04 13;17(4):233-250. Epub 2019 Dec 13.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.

Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody-drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.
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http://dx.doi.org/10.1038/s41571-019-0299-9DOI Listing
April 2020

FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer.

Proc Natl Acad Sci U S A 2019 Dec 11. Epub 2019 Dec 11.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030;

Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER/HER2 metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α-dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
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http://dx.doi.org/10.1073/pnas.1911584116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936436PMC
December 2019

TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer.

Clin Cancer Res 2020 02 29;26(4):821-827. Epub 2019 Oct 29.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Purpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR.

Patients And Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR.

Results: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1-2 diarrhea and acneiform rash being the most common toxicities.

Conclusions: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0851DOI Listing
February 2020

Evaluation of the Predictive Role of Tumor Immune Infiltrate in Patients with HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2 Therapy without Chemotherapy.

Clin Cancer Res 2020 02 25;26(3):738-745. Epub 2019 Oct 25.

Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.

Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with benefit to trastuzumab and chemotherapy in patients with early-stage HER2 breast cancer. The predictive value of TILs, TIL subsets, and other immune cells in patients receiving chemotherapy-sparing lapatinib plus trastuzumab treatment is unclear. Hematoxylin and eosin-stained slides ( = 59) were used to score stromal (s-)TILs from pretreatment biopsies of patients enrolled in the neoadjuvant TBCRC006 trial of 12-week lapatinib plus trastuzumab therapy (plus endocrine therapy for ER tumors). A 60% threshold was used to define lymphocyte-predominant breast cancer (LPBC). Multiplexed immunofluorescence (m-IF) staining (CD4, CD8, CD20, CD68, and FoxP3) and multispectral imaging were performed to characterize immune infiltrates in single formalin-fixed paraffin-embedded slides ( = 33).

Results: The pathologic complete response (pCR) rate was numerically higher in patients with LPBC compared with patients with non-LPBC (50% vs. 19%, = 0.057). Unsupervised hierarchical clustering of the five immune markers identified two patient clusters with different responses to lapatinib plus trastuzumab treatment (pCR = 7% vs. 50%, for cluster 1 vs. 2 respectively; = 0.01). In multivariable analysis, cluster 2, characterized by high CD4, CD8, CD20 s-TILs, and high CD20 intratumoral TILs, was independently associated with a higher pCR rate ( = 0.03). Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by s-CD4, intratumoral (i-) CD4, and i-CD20 TILs.

Conclusions: LPBC was marginally associated with higher pCR rate than non-LPBC in patients with lapatinib plus trastuzumab treated HER2 breast cancer. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002194PMC
February 2020

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

Clin Breast Cancer 2020 04 22;20(2):145-151.e2. Epub 2019 Aug 22.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

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.
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http://dx.doi.org/10.1016/j.clbc.2019.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035200PMC
April 2020

Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer.

Mol Cancer Res 2019 11 16;17(11):2318-2330. Epub 2019 Aug 16.

Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Despite effective strategies, resistance in HER2 breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2 models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2 breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. IMPLICATIONS: The MVA was found to constitute an escape mechanism of survival and growth in HER2 breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825570PMC
November 2019

Randomized controlled trial of high-dose versus standard-dose vitamin D3 for prevention of aromatase inhibitor-induced arthralgia.

Breast Cancer Res Treat 2019 Sep 19;177(2):427-435. Epub 2019 Jun 19.

Baylor College of Medicine, 6445 Main Street, OPC 24-346, Houston, TX, 77030, USA.

Purpose: Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment.

Methods: We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled.

Results: The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development.

Conclusion: Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.
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http://dx.doi.org/10.1007/s10549-019-05319-4DOI Listing
September 2019

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade.

J Natl Cancer Inst 2020 01;112(1):46-54

Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.

Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.

Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).

Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
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http://dx.doi.org/10.1093/jnci/djz042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850037PMC
January 2020

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.

J Clin Oncol 2019 05 12;37(13):1081-1089. Epub 2019 Mar 12.

1 Dana-Farber Cancer Institute, Boston, MA.

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/m 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.
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http://dx.doi.org/10.1200/JCO.18.01511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494354PMC
May 2019

The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.

Br J Cancer 2019 02 17;120(3):331-339. Epub 2018 Dec 17.

Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Background: The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations.

Methods: Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models.

Results: In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance.

Conclusions: These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models.
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http://dx.doi.org/10.1038/s41416-018-0354-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353941PMC
February 2019

Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer.

Nat Med 2018 05 26;24(4):505-511. Epub 2018 Mar 26.

Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer diagnosed in more than 200,000 women each year and is recalcitrant to targeted therapies. Although TNBCs harbor multiple hyperactive receptor tyrosine kinases (RTKs), RTK inhibitors have been largely ineffective in TNBC patients thus far. We developed a broadly effective therapeutic strategy for TNBC that is based on combined inhibition of receptors that share the negative regulator PTPN12. Previously, we and others identified the tyrosine phosphatase PTPN12 as a tumor suppressor that is frequently inactivated in TNBC. PTPN12 restrains several RTKs, suggesting that PTPN12 deficiency leads to aberrant activation of multiple RTKs and a co-dependency on these receptors. This in turn leads to the therapeutic hypothesis that PTPN12-deficient TNBCs may be responsive to combined RTK inhibition. However, the repertoire of RTKs that are restrained by PTPN12 in human cells has not been systematically explored. By methodically identifying the suite of RTK substrates (MET, PDGFRβ, EGFR, and others) inhibited by PTPN12, we rationalized a combination RTK-inhibitor therapy that induced potent tumor regression across heterogeneous models of TNBC. Orthogonal approaches revealed that PTPN12 was recruited to and inhibited these receptors after ligand stimulation, thereby serving as a feedback mechanism to limit receptor signaling. Cancer-associated mutation of PTPN12 or reduced PTPN12 protein levels diminished this feedback mechanism, leading to aberrant activity of these receptors. Restoring PTPN12 protein levels restrained signaling from RTKs, including PDGFRβ and MET, and impaired TNBC survival. In contrast with single agents, combined inhibitors targeting the PDGFRβ and MET receptors induced the apoptosis in TNBC cells in vitro and in vivo. This therapeutic strategy resulted in tumor regressions in chemo-refractory patient-derived TNBC models. Notably, response correlated with PTPN12 deficiency, suggesting that impaired receptor feedback may establish a combined addiction to these proto-oncogenic receptors. Taken together, our data provide a rationale for combining RTK inhibitors in TNBC and other malignancies that lack receptor-activating mutations.
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http://dx.doi.org/10.1038/nm.4507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675908PMC
May 2018

Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial.

J Clin Oncol 2018 04 14;36(11):1073-1079. Epub 2018 Feb 14.

Irene L. Wapnir, Stanford University School of Medicine, Stanford, CA; Karen N. Price and Shari Gelber, Frontier Science and Technology Research Foundation, Richard D. Gelber, Frontier Science and Technology Research Foundation, Dana-Farber Cancer Institute, Harvard TH Chan School of Public Health, Harvard Medical School, Meredith M. Regan, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Stewart J. Anderson, University of Pittsburgh Graduate School of Public Health; Priya Rastogi, University of Pittsburgh Cancer Institute; Norman Wolmark, Allegheny Health Network Cancer Institute, Pittsburgh, PA; André Robidoux, Centre Hospitalier de l'Université de Montréal, Montréal, Quebec; Alexander H.G. Paterson, Tom Baker Cancer Centre, Calgary, Alberta, Canada; Miguel Martín, CIBERONC, Instituto de Investigación Sanitaria Gregorio Marañon, Universidad Complutense, Madrid; José Manuel Baena-Cañada, Hospital Puerta del Mar, Cádiz, Spain; Johan W.R. Nortier, Leids Universitair Medisch Centrum, Leiden, Netherlands; Mothaffar F. Rimawi, Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, TX; István Láng, National Institute of Oncology, Budapest, Hungary; Beat Thürlimann, Kantonsspital, St. Gallen; Stefan Aebi, Lucerne Cantonal Hospital and University of Bern, Switzerland; Eleftherios P. Mamounas, Orlando Health University of Florida Health Cancer Center, Orlando, FL; Charles E. Geyer Jr, Virginia Commonwealth University Massey Cancer Center, Richmond, VA; and Alan S. Coates, University of Sydney, Sydney, Australia.

Purpose Isolated locoregional recurrence (ILRR) predicts a high risk of developing breast cancer distant metastases and death. The Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial investigated the effectiveness of chemotherapy (CT) after local therapy for ILRR. A report at 5 years of median follow-up showed significant benefit of CT for estrogen receptor (ER)-negative ILRR, but additional follow-up was required in ER-positive ILRR. Patients and Methods CALOR was an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomly assigned to receive CT or no CT and stratified by prior CT, hormone receptor status, and location of ILRR. Patients with hormone receptor-positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-human epidermal growth factor receptor 2 therapy was optional. End points were disease-free survival (DFS), overall survival, and breast cancer-free interval. Results From August 2003 to January 2010, 162 patients were enrolled: 58 with ER-negative and 104 with ER-positive ILRR. At 9 years of median follow-up, 27 DFS events were observed in the ER-negative group and 40 in the ER-positive group. The hazard ratios (HR) of a DFS event were 0.29 (95% CI, 0.13 to 0.67; 10-year DFS, 70% v 34%, CT v no CT, respectively) in patients with ER-negative ILRR and 1.07 (95% CI, 0.57 to 2.00; 10-year DFS, 50% v 59%, respectively) in patients with ER-positive ILRR ( P = .013). HRs were 0.29 (95% CI, 0.13 to 0.67) and 0.94 (95% CI, 0.47 to 1.85), respectively, for breast cancer-free interval ( P = .034) and 0.48 (95% CI, 0.19 to 1.20) and 0.70 (95% CI, 0.32 to 1.55), respectively, for overall survival ( P = .53). Results for the three end points were consistent in multivariable analyses adjusting for location of ILRR, prior CT, and interval from primary surgery. Conclusion The final analysis of CALOR confirms that CT benefits patients with resected ER-negative ILRR and does not support the use of CT for ER-positive ILRR.
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http://dx.doi.org/10.1200/JCO.2017.76.5719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891132PMC
April 2018

Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27.

Clin Breast Cancer 2018 02 16;18(1):78-87. Epub 2017 Oct 16.

Department of Internal Medicine, Mayo Clinic, Rochester, MN.

Background: Approximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA.27 study, we assessed several factors potentially associated with AIA.

Patients And Methods: MA.27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation. We also examined 9 baseline inflammatory cytokines: interleukin (IL)-1β, IL-6, tumor necrosis factor-α, interferon (IFN)γ, IL-10, IL-12p70, IL-17, IL-23, and chemokine ligand (CCL)-20. Finally, we analyzed the multivariate effects of baseline factors: vitamin D level, previously identified musculoskeletal single nucleotide polymorphisms, age, body mass index, and vitamin D receptor (VDR) Fok-I variant genotype on AIA development.

Results: Changes in vitamin D from baseline to 6 months were not significantly different between cases and controls. Elevated inflammatory cytokine levels were not associated with development of AIA. The multivariate model included no clinical factors associated with AIA. However, women with the VDR Fok-I variant genotype were more likely to have a lower IL-1β level (P = .0091) and less likely to develop AIA after 6 months of AI compared with those with the wild type VDR (P < .0001).

Conclusion: In this nested case-control correlative study, vitamin D levels were not significantly associated with development of AIA; however, patients with the Fok-I VDR variant genotype were more likely to have a significant reduction in IL-1β level, and less likely to develop AIA.
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http://dx.doi.org/10.1016/j.clbc.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469602PMC
February 2018

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.

Breast Cancer Res Treat 2018 02 7;167(3):731-740. Epub 2017 Nov 7.

Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA.

Purpose: Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.

Patients And Methods: Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR).

Results: Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006).

Conclusion: PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.
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http://dx.doi.org/10.1007/s10549-017-4533-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821069PMC
February 2018

De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance.

Breast 2017 Aug 4;34 Suppl 1:S19-S26. Epub 2017 Jul 4.

Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Electronic address:

Overexpression and/or gene amplification of HER2, a crucial member of the HER family of four receptors, occur in about 15-20% of breast cancers and define an aggressive subtype of the disease. Activated HER homo and heterodimers govern a complex and redundant downstream signaling network that regulates cell survival and metastasis. Despite treatment with effective HER2-targeted therapies, many HER2-positive tumors fail to respond, or initially respond but eventually develop resistance. One of the upfront reasons for this treatment failure is failure to accurately select the tumors that are truly dependent on HER2 for survival and so would benefit the most from HER2-targeted therapy. In these truly HER2-addicted tumors (i.e. physiologically dependent), resistance could be the result of an incomplete inhibition of signaling at the HER receptor layer. In this regard, preclinical and clinical studies have documented the superiority of combination anti-HER2 therapy over single agent therapy to achieve a more comprehensive inhibition of the various HER receptor dimers. HER2 can be further activated or reactivated by mutations or other alterations in HER2 itself, or in other HER family members. Even when a complete and sustained HER inhibition is achieved, resistance to anti-HER therapy can arise by other somewhat dominant mechanisms, including preexisting or emerging alternative signaling pathways such as the estrogen receptor, deregulated downstream signaling components, especially of the PI3K pathway, and the tumor immune microenvironment. Most of the clinical trials that have investigated the efficacy of anti-HER2 therapies took place in the background of aggressive chemotherapy regimens, thus confounding the identification of key factors of resistance to the anti-HER2 treatments. Recent studies, however, have suggested that some HER2-amplified tumors may benefit from anti-HER2 therapy combined with only a single chemotherapy agent or in the absence of any chemotherapy. This de-escalation approach, a promising therapeutic strategy, is currently being explored in the clinic. In this review, we summarize the major molecular determinants that play a crucial role in influencing tumor response and resistance to HER2-targeted therapy, and discuss the growing need for patient stratification in order to facilitate the development of de-escalation strategies using HER2-targeted therapy alone with no chemotherapy.
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http://dx.doi.org/10.1016/j.breast.2017.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050048PMC
August 2017

HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2 Breast Cancer.

Clin Cancer Res 2017 Sep 9;23(17):5123-5134. Epub 2017 May 9.

Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Resistance to anti-HER2 therapies in HER2 breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2 breast cancer can reactivate the HER network under potent HER2-targeted therapies. Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER/HER2 BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. and experiments were performed to test alternative therapies for mutant HER2 inhibition. Genomic analyses revealed that the L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2-irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by L755S and HER2 reactivation through acquisition of the L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762201PMC
September 2017

Retrospective review of genomic testing in breast cancer: Does it improve outcome?

Breast Cancer Res Treat 2017 May 21;163(1):191-195. Epub 2017 Feb 21.

Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

Purpose: Tumor genomic testing has become widely available in many clinical settings. However, we do not yet understand how to best harness the information yielded from this testing. We retrospectively investigated the clinical courses of 24 patients who underwent tumor genomic testing to determine whether targeted therapy is associated with improved progression free survival (PFS) compared to standard therapy.

Methods: The patient population comprised metastatic breast cancer patients who underwent tumor genomic testing (testing biopsy specimens of primary or metastatic lesions for 50 commonly mutated genes) at our institution between September 1, 2010 and June 1, 2015. Through retrospective chart review, we compared PFS for those patients who received targeted therapy based on their genomic testing results, and those who did not.

Results: The median PFS was 5.7 months for those who received targeted therapy versus 5.4 months for those who did not (p = 0.6). There was no statistically significant difference in PFS between the two groups.

Conclusions: In this relatively small group, the PFS was markedly similar between the targeted therapy and standard therapy groups. Currently, there is no clear evidence to incorporate tumor genomic testing into routine clinical practice.
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http://dx.doi.org/10.1007/s10549-017-4154-3DOI Listing
May 2017

Metastatic human epidermal growth factor receptor 2-positive breast cancer: Management, challenges, and future directions.

Curr Probl Cancer 2016 Mar - Aug;40(2-4):117-129. Epub 2016 Sep 19.

Department of Medicine, Lester and Sue Smith Breast Center, and Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, Texas 77030.

HER2 is over-expressed or amplified in 15-20% of breast cancer. Significant progress has been made in the treatment of metastatic HER2+ breast cancer. This is largely due to successful targeting of the HER2 pathway. There are several approved agents in the metastatic setting. However, treatment resistance frequently develops and tumors eventually progress. In recent years, our understanding of mechanisms of resistance has evolved. It is generally accepted now that HER2-positive breast cancer is not one disease. New therapeutic strategies and a tailored approach to management are necessary to maximize patient outcomes and minimize toxicity.
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http://dx.doi.org/10.1016/j.currproblcancer.2016.09.005DOI Listing
December 2017

Spatial Proximity to Fibroblasts Impacts Molecular Features and Therapeutic Sensitivity of Breast Cancer Cells Influencing Clinical Outcomes.

Cancer Res 2016 11 26;76(22):6495-6506. Epub 2016 Sep 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Using a three-dimensional coculture model, we identified significant subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAF). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2 breast cancer cells to lapatinib both in vitro and in vivo, including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2 breast tumors lead to a significant increase of phospho-STAT3 cancer cells and a decrease in the spatial proximity of proliferating (Ki67) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance. Cancer Res; 76(22); 6495-506. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344673PMC
November 2016

FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer.

Proc Natl Acad Sci U S A 2016 10 6;113(43):E6600-E6609. Epub 2016 Oct 6.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Medicine, Baylor College of Medicine, Houston, TX 77030;

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)-chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.
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http://dx.doi.org/10.1073/pnas.1612835113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087040PMC
October 2016

TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis.

Clin Cancer Res 2016 Dec 10;22(23):5706-5712. Epub 2016 May 10.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases.

Experimental Design: A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured.

Results: A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PR). The clinical benefit rate [PRs + stable disease (SD) ≥ 6 months] in bone was 8/22 (36%). Median time to treatment failure was 2.70 months [95% confidence interval (CI), 1.84-5.72] in the general cohort, 3.65 months (95% CI, 1.97-7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI, 0.30-NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR-positive status, and pretreatment high NTx levels.

Conclusions: Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2845DOI Listing
December 2016

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

J Clin Oncol 2016 Mar 1;34(9):945-52. Epub 2016 Feb 1.

Rachel A. Freedman, Rebecca S. Gelman, Christina Herold, Nicole Ryabin, Sarah Farooq, Elizabeth Lawler, Ian E. Krop, Eric P. Winer, and Nancy U. Lin, Dana-Farber Cancer Institute; Beverly Moy, Massachusetts General Hospital; Alarice Lowe and Nathalie Y.R. Agar, Brigham and Women's Hospital, Boston, MA; Jeffrey S. Wefel, Kenneth R. Hess, and Nuhad Ibrahim, The University of Texas MD Anderson Cancer Center; Polly A. Niravath and Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; Michelle E. Melisko, University of California, San Francisco, San Francisco, CA; Roisin M. Connolly and Antonio C. Wolff, Johns Hopkins University, Baltimore, MD; Catherine H. Van Poznak, University of Michigan, Ann Arbor, MI; Shannon L. Puhalla, University of Pittsburgh Cancer Institute and Magee-Women's Hospital, Pittsburgh, PA; Kimberly L. Blackwell, Duke University Medical Center, Durham, NC; and Minetta C. Liu, Mayo Clinic, Rochester, MN.

Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial.

Patients And Methods: Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders.

Results: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time.

Conclusion: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.
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http://dx.doi.org/10.1200/JCO.2015.63.0343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070554PMC
March 2016

Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003).

J Clin Oncol 2015 Aug 13;33(24):2623-31. Epub 2015 Jul 13.

Nancy U. Lin, Hao Guo, Nicole Ryabin, Julie S. Najita, William T. Barry, Ian E. Krop, Eric P. Winer, and Annick D. Van den Abbeele, Dana-Farber Cancer Institute; Andrea L. Richardson and Annick D. Van den Abbeele, Brigham and Women's Hospital, Boston, MA; Jeffrey T. Yap, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; Ingrid A. Mayer and Carlos L. Arteaga, Vanderbilt-Ingram Cancer Center, Nashville, TN; Carla I. Falkson, University of Alabama, Birmingham, AL; Timothy J. Hobday, Mayo Clinic, Rochester, MN; E. Claire Dees, University of North Carolina, Chapel Hill, NC; Rita Nanda, University of Chicago, Chicago, IL; Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; and Antonio C. Wolff, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.

Purpose: Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes.

Patients And Methods: Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored.

Results: Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2).

Conclusion: Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.
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http://dx.doi.org/10.1200/JCO.2014.60.0353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534525PMC
August 2015

Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy.

Clin Cancer Res 2015 Sep 26;21(17):3995-4003. Epub 2015 May 26.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas.

Purpose: To investigate the direct effect and therapeutic consequences of epidermal growth factor receptor 2 (HER2)-targeting therapy on expression of estrogen receptor (ER) and Bcl2 in preclinical models and clinical tumor samples.

Experimental Design: Archived xenograft tumors from two preclinical models (UACC812 and MCF7/HER2-18) treated with ER and HER2-targeting therapies and also HER2+ clinical breast cancer specimens collected in a lapatinib neoadjuvant trial (baseline and week 2 posttreatment) were used. Expression levels of ER and Bcl2 were evaluated by immunohistochemistry and Western blot analysis. The effects of Bcl2 and ER inhibition, by ABT-737 and fulvestrant, respectively, were tested in parental versus lapatinib-resistant UACC812 cells in vitro.

Results: Expression of ER and Bcl2 was significantly increased in xenograft tumors with acquired resistance to anti-HER2 therapy compared with untreated tumors in both preclinical models (UACC812: ER P = 0.0014; Bcl2 P < 0.001 and MCF7/HER2-18: ER P = 0.0007; Bcl2 P = 0.0306). In the neoadjuvant clinical study, lapatinib treatment for 2 weeks was associated with parallel upregulation of ER and Bcl2 (Spearman coefficient: 0.70; P = 0.0002). Importantly, 18% of tumors originally ER-negative (ER(-)) converted to ER(+) upon anti-HER2 therapy. In ER(-)/HER2(+) MCF7/HER2-18 xenografts, ER reexpression was primarily observed in tumors responding to potent combination of anti-HER2 drugs. Estrogen deprivation added to this anti-HER2 regimen significantly delayed tumor progression (P = 0.018). In the UACC812 cells, fulvestrant, but not ABT-737, was able to completely inhibit anti-HER2-resistant growth (P < 0.0001).

Conclusions: HER2 inhibition can enhance or restore ER expression with parallel Bcl2 upregulation, representing an ER-dependent survival mechanism potentially leading to anti-HER2 resistance.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558260PMC
September 2015

Resistance to Anti-HER2 Therapies in Breast Cancer.

Am Soc Clin Oncol Educ Book 2015 :e157-64

From the Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center at Baylor College of Medicine, Houston, TX.

HER2 is amplified or overexpressed in 20% to 25% of breast cancers. HER2 is a redundant, robust, and powerful signaling pathway that represents an attractive therapeutic target. Anti-HER2 therapy in the clinic has resulted in significant improvements in patient outcomes and, in recent years, combinations of anti-HER2 therapies have been explored and carry great promise. However, treatment resistance remains a problem. Resistance can be mediated, among others, by pathway redundancy, reactivation, or the utilization of escape pathways. Understanding mechanisms of resistance can lead to better therapeutic strategies to overcome resistance and optimize outcomes.
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http://dx.doi.org/10.14694/EdBook_AM.2015.35.e157DOI Listing
February 2016

Targeting HER2 for the treatment of breast cancer.

Annu Rev Med 2015 ;66:111-28

Lester and Sue Smith Breast Center and the Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, 77030; email: , ,

HER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1-4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.
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http://dx.doi.org/10.1146/annurev-med-042513-015127DOI Listing
September 2015

Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis.

Breast Cancer Res 2015 Jan 9;17. Epub 2015 Jan 9.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.

Introduction: Real-time monitoring of biologic changes in tumors may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in cancer patients pose major hurdles. The goal of this study was to determine whether breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes.

Methods: CTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counterstaining of red blood cell-lysed blood and bone marrow fractions, respectively. The rate of lung metastases (LM) was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher's Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed by using the expression arrays of primary tumors from different PDX lines and subsequently overlapped to identify common genes.

Results: In total, 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present as either single cells or clusters, were detected in 83% (15 of 18) and 62.5% (10 to16) of the lines, respectively. A positive association was noted between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 of 18 (50%) lines, of which all nine had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the two genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified four genes (HLA-DP1A, GJA1, PEG3, and XIST). This four-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients.

Conclusion: This study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases.
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http://dx.doi.org/10.1186/s13058-014-0508-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318479PMC
January 2015