Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

Brasó-Maristany, Fara; Griguolo, Gaia; Pascual, Tomás; Paré, Laia; Nuciforo, Paolo; Llombart-Cussac, Antonio; Bermejo, Begoña; Oliveira, Mafalda; Morales, Serafín; Martínez, Noelia; Vidal, María; Adamo, Bárbara; Martínez, Olga; Pernas, Sònia; López, Rafael; Muñoz, Montserrat; Chic, Núria; Galván, Patricia; Garau, Isabel; Manso, Luis; Alarcón, Jesús; Martínez, E.; Gregorio, Sara; Gomis, Roger R.; Villagrasa, Patricia; Cortés, Javier; Ciruelos, Eva; Prat, Aleix

doi:10.1038/s41467-019-14111-3

Cited by 88 publications

(69 citation statements)

References 41 publications

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“…8). Unlike what has been reported previously 30 , conversion to normal-like was not associated with pCR (34.2% vs 33.3%), and conversion to luminal A was infrequent, suggesting that the addition of endocrine therapy may have driven this conversion in the previous study 35 . Integrative subtype was more stable than intrinsic subtype across targeted therapy, perhaps due to it being less dependent on microenvironmental composition: integrative subtype changed in 25.8% of tumors (vs 53.9% for intrinsic subtype; χ2 p = 2.4e-4), with 82.6% of these converting to integrative subtype 9 (IC9, likely misclassification of lower cellularity tumors) ( Fig.…”

Section: Resultscontrasting

confidence: 74%

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07)

et al. 2020

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In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

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Section: Resultscontrasting

confidence: 74%

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07)

et al. 2020

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“…The PAMELA trial found that dual HER2 blockade led to a decrease in CCND1 mRNA in HER2+/HR+ breast tumors (experimental arm), suggesting that the combination therapy was more efficient at arresting the cell cycle and preventing tumor growth in patients with BC. 22 Our study also discovered an association between insurance type and outcome; patients using government-provided insurance exhibited OS, when compared with patients using other types of insurance coverage. While these findings are likely a product of multiple sociodemographic and/or socioeconomic factors and require further exploration, they appear consistent with previously reported literature suggesting that patients with Medicaid had higher mortality rates than privately insured patients following colorectal cancer surgery, 23 and that primary payer status affects patient mortality for most major cancer surgical operations.…”

Section: Breast Cancer: Basic and Clinical Researchsupporting

confidence: 56%

Endocrine Therapy Plus Anti-HER2 Therapy as Adjuvant Systemic Therapy for Luminal HER2-Positive Breast Cancer: An Analysis of the National Cancer Database

Nahleh

Elimimian

Elson

et al. 2020

Breast Cancer�(Auckl)

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Background: Guidelines regarding the usage of adjuvant systemic therapy in patients with small human epidermal growth factor receptor 2 (HER2)-positive and estrogen receptor/progesterone receptor–positive (luminal HER2 positive) tumors are nonspecific. Outcomes of chemotherapy followed by endocrine therapy (ET), with or without anti-HER2 therapy, vs ET alone (no chemotherapy) have not been widely studied in this disease subtype. We sought to examine the usage and outcomes of adjuvant systemic therapy (ET vs chemotherapy with or without trastuzumab) in stage I luminal HER2-positive breast cancer (BC), based on the large National Cancer Database. Methods: We conducted a retrospective analysis of patients with luminal HER2-positive stage I BC, diagnosed between 2010 and 2015, in the United States, using univariable and multivariable logistic regression analyses. The Kaplan-Meier method estimated overall survival (OS). Results: A total of 37 777 patients were included in the analysis; of these, n = 32 594 (86%) received adjuvant ET and n = 5183 (14%) received chemotherapy. Around 40% of all patients received anti-HER2 therapy (trastuzumab). Patients who received trastuzumab had a better 5-year OS (93.4% vs 92.0%, P = .0002) compared with those who did not. Patients who received anti-HER2 therapy plus ET had the best OS rate at 5 years (93.5%, confidence interval [CI]: 89.2%-98%, P < .0001) compared with those receiving anti-HER2 therapy plus chemotherapy (92.7%, CI: 89.4%-96.1%, P < .0001). Conclusions: Most patients in the United States, with stage I luminal HER2 positive BC, received ET, not chemotherapy but most of them do not receive anti-HER2 therapy resulting in inferior outcome. Future trials exploring the de-escalation of systemic adjuvant therapy for early-stage luminal HER2-positive BC to ET plus anti-HER2 therapy would be desirable.

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“…All the animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and regulations for Laboratory Animal Science Center, Fudan University which include items for the welfare of the animals. Each 6-week-old male BALB/c nude mice (n=5) was injected subcutaneously with a total of 1×10 6 Lentivirus-infected MDA-MB-231 cells suspended in Matrigel (volume, 1:1; Corning, Inc., 356234, NY, USA). 28 days later, mice were euthanized and sections of tumor xenografts were dissected and weighed.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…2,3 Breast cancer is a heterogeneous disease that can be classified into several subtypes based on histological characteristics and the expression of genetic markers. 4 Despite recent advances in breast cancer therapy, including chemotherapy, endocrine therapy, and HER2-targeted therapies, [5][6][7] the high proliferative, invasive, metastatic potential of breast cancer cells, as well as the development of drug resistance, are major causes of therapeutic failure and poor survival in patients with breast cancer. 8,9 Therefore, the development of novel therapeutic approaches is an urgent need.…”

Section: Introductionmentioning

confidence: 99%

<p>The Clinical Relevance and Function of Krüppel-Like Factor 16 in Breast Cancer</p>

Bang¹,

Li²,

Zhang³

et al. 2020

CMAR

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Background: Krüppel-like factor 16 (KLF16), a member of the KLF family, is involved in metabolism and regulation of the endocrine system and has emerging roles in tumor progression. However, the expression of KLF16 and its role in breast cancer are elusive. Methods: We investigated the expression and prognostic value of KLFs in breast cancer using data acquired from the TCGA BRCA dataset and the Kaplan-Meier plotter dataset. The protein levels of KLF16 in breast specimens were detected by immunohistochemistry (IHC). KLF16 silencing using shRNAs was performed to explore the effects of KLF16 on breast cancer cell growth, migration, and invasion. The expression of EMT markers in cells manipulated for KLF16 expression was assessed by Western blotting. Results: Using publicly available dataset and specimens from breast cancer patients, we found that the expression levels of KLF16 were significantly higher in tumor tissues and that high levels of KLF16 were associated with poor prognosis in breast cancer patients. Moreover, KLF16 expression levels had relation to several clinicopathological parameters of breast cancer, including the molecular subtype and histological grade. Importantly, knockdown of KLF16 dramatically suppressed cell proliferation both in vitro and in vivo. Also, KLF16 deletion impaired migration, and invasion in breast cancer cells, and suppressed epithelial-mesenchymal transition (EMT). Conclusion: Our results suggest that KLF16 has important oncogenic functions in breast cancer and that the expression levels of KLF16 are associated with prognosis in breast cancer patients. Our findings also suggest that KLF16 is involved in proliferation, migration, and invasion in breast cancer cells. Thus, KLF16 might be a promising prognostic marker and a therapeutic target for breast cancer.

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Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

Cited by 88 publications

References 41 publications

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07)

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07)

Endocrine Therapy Plus Anti-HER2 Therapy as Adjuvant Systemic Therapy for Luminal HER2-Positive Breast Cancer: An Analysis of the National Cancer Database

<p>The Clinical Relevance and Function of Krüppel-Like Factor 16 in Breast Cancer</p>

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