HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab

Ithimakin, Suthinee; Day, Kathleen C.; Malik, Fayaz; Zen, Qin; Dawsey, Scott J.; Bersano-Begey, Tom; Quraishi, Ahmed A.; Ignatoski, Kathleen M. Woods; Daignault, Stephanie; Davis, April; Hall, Christopher L.; Palanisamy, Nallasivam; Heath, Amber; Tawakkol, Nader; Luther, Tahra; Clouthier, Shawn G.; Chadwick, Whitney; Day, Mark L.; Kleer, Celina G.; Thomas, Dafydd G.; Hayes, Daniel F.; Korkaya, Hasan; Wicha, Max S.

doi:10.1158/0008-5472.can-12-3349

Cited by 215 publications

(181 citation statements)

References 45 publications

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“…Therapies targeting stem-like breast cancer cells may best be administered in the adjuvant setting to obtain maximum clinical benefit (46), especially since residual tumors after conventional treatment show enrichment for tumor-initiating cells (14). We now show that driving PUMA expression with therapies such as Src inhibitors selectively targets αvβ3 + Slug + stem-like tumor cells.…”

Section: Slugmentioning

confidence: 73%

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

Sun¹,

Lesperance²,

Wettersten³

et al. 2017

Journal of Clinical Investigation

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Section: Slugmentioning

confidence: 73%

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

Sun¹,

Lesperance²,

Wettersten³

et al. 2017

Journal of Clinical Investigation

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“…In contrast, age was not associated with increased risk of ER−/PR+ disease among Luminal B cases. This observation may be explained by findings using experimental models, that overexpression of HER2 supports aggressive tumor growth in luminal breast cancers 22.…”

Section: Discussionmentioning

confidence: 99%

HER2 status and disparities in luminal breast cancers

et al. 2016

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National Comprehensive Care Network guidelines for adjuvant treatment of invasive breast cancer are based on HER2 and hormone receptor (HR) status, where HR+ disease encompasses all estrogen receptor (ER)+ and/or progesterone receptor (PR)+ tumors. We sought to explore clinical and demographic differences among patients with HR+ breast cancer subtypes, and the role of HER2 status, age, race/ethnicity, and socioeconomic status (SES) in disease risk. We evaluated breast cancer subtype distribution, defined by HR and HER2 status, using patient clinical, demographic, and socioeconomic characteristics. Differences in HR categories by demographic and tumor characteristics were examined using chi‐squared tests. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) to quantify associations between breast cancer HR status and demographic factors. We found that differences in HR+ (ER−/PR+ vs. ER+/PR− or ER+/PR+) tumor biology are likely clinically significant and may play a role in breast cancer, regardless of HER2 status. While clinical and patient characteristics differed within each luminal subtype, we found disparities in SES only among Luminal A (HR+/HER2−) tumors. Among HR+/HER2− cases, we observed that ER−/PR+ patients tend to live in areas of higher poverty (OR = 1.20, 95% CI = 1.03–1.40) and are 70% more likely to be aged 50 years or older. However, this pattern was not found in women with Luminal B (HR+/HER2+) disease (Poverty OR = 0.98, 95% CI = 0.76–1.27; Age OR = 1.01, 95% CI = 0.81–1.26). Racial/ethnic disparities among non‐Hispanic black and Hispanic women persisted across HR+/HER2− cases compared to non‐Hispanic white women. Our findings suggest that while race/ethnicity and SES are correlated, each plays an independent role in contributing to disease among Luminal A tumors. Further study is needed to investigate how tumor biology, race/ethnicity, and socioeconomic disparities among HR+/HER2− cases may contribute to poorer patient prognosis.

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“…23 Furthermore, bone metastases of breast cancer frequently overexpressed HER2 protein in the absence of ERBB2 gene amplification. 23 Therefore, disseminated CSCs or bone micrometastatic cells may be responsive to trastuzumab treatment regardless of HER2 status of the primary tumor. Thus, patients with HER2-negative tumors could benefit from trastuzumab in the adjuvant setting but not in the neoadjuvant or metastatic setting when pCR or PFS is the clinical end point.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

Pogue–Geile

Song

Jeong

et al. 2015

JCO

104

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Purpose Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) –positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31. Patients and Methods Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point. Results Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64). Conclusion Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.

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HER2 Drives Luminal Breast Cancer Stem Cells in the Absence of HER2 Amplification: Implications for Efficacy of Adjuvant Trastuzumab

Cited by 215 publications

References 45 publications

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

HER2 status and disparities in luminal breast cancers

Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

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