Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer

Fujii, Takeo; Kogawa, Takahiro; Dong, Wei; Şahin, Ayşegül; Moulder, Stacy L.; Litton, Jennifer K.; Tripathy, Debasish; Inomata, Takayuki; Hunt, Kelly K.; Pusztai, Lajos; Lim, Bora; Shen, Yudao; Ueno, Naoto T.

doi:10.1093/annonc/mdx397

Cited by 126 publications

(108 citation statements)

References 31 publications

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“…Previous analyses have already highlighted that tumors with ER < 10% clinically behave as ER < 1% tumors. 35 Along with the results presented in this paper, these data indicate that for clinical purposes, tumors with ER < 10% and HER2/neu 0 or 1 + should be considered as TNBC. Furthermore, as reported in other analyses, 27 3 out of 34 (8.8%) BRCA1-related tumors presented a more rare non-ductal histotype (in our study one medullary, one papillary and one lobular).…”

Section: Discussionsupporting

confidence: 73%

BRCA detection rate in an Italian cohort of luminal early-onset and triple-negative breast cancer patients without family history: when biology overcomes genealogy.

Toss

Molinaro

Venturelli

et al. 2020

Preprint

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BACKGROUND: NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. This analysis aimed to evaluate the rate of BRCA mutations in triple-negative breast cancer (TNBC) patients diagnosed ≤60 years and luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family history. METHODS: 159 TNBC patients diagnosed ≤60 years and 109 luminal-like BC patients diagnosed ≤35 years without family history were retrospectively identified. Mutation prevalence and clinical-pathological characteristics associated with mutational status were evaluated. RESULTS: In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1 and 1.2% BRCA2). BRCA1-related TNBC patients were younger (p <0.001). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31-40, 16.1% for those aged 41-50 and 7.9% for those between 51 and 60 years of age. A total of 40% of patients with estrogen receptor (ER) 1-9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (1.8% BRCA1 and 4.6% BRCA2). Mutation prevalence was 0% 0-25 years, 9% 26-30 years and 6% 31-35 years. BRCA2-positive luminal-like early-onset BCs were more likely associated with low progesterone receptor (PR) expression (p = 0.049). CONCLUSIONS: BRCA genetic testing is recommended in TNBC diagnosed ≤ 60 years, regardless of cancer family history, histotype and by using immunohistochemical staining <10% of nuclei for both ER and/PR as a cut-off. In luminal-like early-onset BC patients, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes.

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Section: Discussionsupporting

confidence: 73%

BRCA detection rate in an Italian cohort of luminal early-onset and triple-negative breast cancer patients without family history: when biology overcomes genealogy.

Toss

Molinaro

Venturelli

et al. 2020

Preprint

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“…Only 33.3% of patients with 1%-9% HR-positive disease received endocrine therapy, versus 64.2% of patients with tumors with 10%-100% HR positivity. Data from recent retrospective studies in early breast cancer suggest that patients with primary breast tumors expressing ER in 1%-9% of cells may derive limited or no benefits from endocrine therapy (16,17). While the number of patients with 1%-9% HR positivity in SystHERs (n ¼ 60) is too limited to assess the association of specific treatment regimens with clinical outcomes, future studies should investigate whether low HR positivity in patients with HER2-positive MBC is predictive of clinical benefits from endocrine therapy.…”

Section: Discussionmentioning

confidence: 99%

Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive Metastatic Breast Cancer by Hormone Receptor Status from SystHERs

Cobleigh

Yardley

Brufsky

et al. 2020

Clinical Cancer Research

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Purpose: We report treatments and outcomes in a contemporary patient population with HER2-positive metastatic breast cancer (MBC) by hormone receptor (HR) status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). Experimental Design: SystHERs (NCT01615068) was an observational, prospective registry study of U.S.-based patients with newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes. Results: Of 977 eligible patients (enrolled from 2012 to 2016), 70.1% (n ¼ 685) had HR-positive and 29.9% (n ¼ 292) had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/ 685) received HER2-targeted therapy þ chemotherapy þ sequential endocrine therapy. Patients with HR-positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs 43.4 months; hazard ratio, 0.70; 95% confidence interval, 0.56-0.87). Compared with patients with high HR-positive staining (10%-100%, n ¼ 550), those with low HR-positive staining (1%-9%, n ¼ 60) received endocrine therapy less commonly (64.2% vs 33.3%) and had shorter median OS (53.8 vs 40.1 months). Similar median OS (43.4 vs 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%-9%). Conclusions: Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in this real-world setting received such treatment. Patients with low tumor HR positivity (1%-9%) had lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%-100%).

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“…Many of these so-called "borderline" tumors have pathological features of ER-negative tumors, with survival outcomes intermediate between ER-negative and ER-positive cases. [7][8][9][10][11][12][13][14][15] As a result, identifying ER-borderline tumors that are responsive to endocrine therapy has been a persistent clinical challenge. In 2010, the American Society of Clinical Oncology and College of American Pathologists issued clinical guidelines classifying ER-positive breast cancers as those with ≥1% staining; in these tumors endocrine therapy is recommended.…”

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confidence: 99%

Borderline Estrogen Receptor–Positive Breast Cancers in Black and White Women

Benefield¹,

Allott

Reeder‐Hayes³

et al. 2019

JNCI: Journal of the National Cancer Institute

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Background Some breast tumors expressing greater than 1% and less than 10% estrogen receptor (ER) positivity (ER-borderline) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants. Methods Using the Carolina Breast Cancer Study (phase I: 1993–1996; 2: 1996–2001; 3: 2008–2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race, using Kaplan Meier and Cox models. Statistical tests were two-sided. Results ER-borderlines were more frequently basal-like (RFD = +37.7%, 95% confidence interval [CI] = 27.1% to 48.4%) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8% to 68.0%) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0% to 43.3%). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR] = 2.03, 95% CI = 0.89% to 4.65%), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84% to 6.02%). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09% to 7.04%). Conclusions ER-borderline tumors were genomically heterogeneous, with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response.

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Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer

Cited by 126 publications

References 31 publications

BRCA detection rate in an Italian cohort of luminal early-onset and triple-negative breast cancer patients without family history: when biology overcomes genealogy.

BRCA detection rate in an Italian cohort of luminal early-onset and triple-negative breast cancer patients without family history: when biology overcomes genealogy.

Baseline Characteristics, Treatment Patterns, and Outcomes in Patients with HER2-Positive Metastatic Breast Cancer by Hormone Receptor Status from SystHERs

Borderline Estrogen Receptor–Positive Breast Cancers in Black and White Women

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