Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2-negative breast cancer

Yoder, Rachel; Kimler, Bruce F.; Staley, Joshua M.; Schwensen, Kelsey; Wang, Yen Y.; Finke, Karissa; O’Dea, Anne; Nye, Lauren; Elia, Manana; Crane, Gregory; McKittrick, Richard; Pluenneke, Robert; Madhusudhana, Sheshadri; Beck, Larry; Shrestha, Anuj; Corum, Larry; Marsico, Mark; Stecklein, Shane R.; Godwin, Andrew K.; Khan, Qamar J.; Sharma, Priyanka

doi:10.1038/s41523-022-00448-4

Cited by 29 publications

(24 citation statements)

References 36 publications

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“…A growing body of literature indicates that HER2/ ERBB2 negative, low ER−PR breast cancer displays clinical characteristics, chemotherapy response, and outcomes similar to TNBC. [22][23][24] The low ER−PR group comprises 8% to 16% of HER2/ERBB2 negative breast cancer and is often excluded from TNBC clinical trials, thus limiting efficacy data for newer therapies in this group. [22][23][24] Although numbers are small, NeoPACT provides some evidence of neoadjuvant chemoimmunotherapy efficacy in the group of patients with low ER−PR.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Sharma,

Stecklein,

Yoder

et al. 2024

JAMA Oncol

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ImportanceAddition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed.ObjectiveTo assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC.Design, Setting, and ParticipantsThis was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022.Intervention or ExposureCarboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles.Main Outcomes and MeasuresPrimary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay.ResultsAmong the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group.Conclusions and RelevanceThe findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC.Trial RegistrationClinicalTrials.gov Identifier: NCT03639948

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Section: Discussionmentioning

confidence: 99%

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Sharma,

Stecklein,

Yoder

et al. 2024

JAMA Oncol

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“…No difference was observed in recurrence-free survival (RFS) and overall survival (OS). Among 358 patients that received neoadjuvant chemotherapy, rates of pathologic complete response (pCR) were similar for TNBC and ERlo groups (49% vs. 51%, respectively, p=0.8) ( 30 )…”

Section: Clinicopathological Features and Molecular Characterization ...mentioning

confidence: 99%

“…Endocrine therapy significantly benefits patients with ER-positive breast cancer but is not devoid of side effects. The collective lack of substantive evidence of benefit in ERlo tumors, associated with the potential adverse impact of ET on quality of life, contributes to low rates of adjuvant ET use in several cohorts ( 30 ). A lack of benefit of ET in patients with ERlo breast cancer was demonstrated in a meta-analysis, which enrolled six studies with more than 16,000 patients ( 40 ).…”

Section: Therapeutic Implications and Recommendationsmentioning

confidence: 99%

Clinical implication of low estrogen receptor (ER-low) expression in breast cancer

Reinert¹,

Cascelli

Resende

et al. 2022

Front. Endocrinol.

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Breast cancer is a heterogeneous disease, and the estrogen receptor (ER) remains the most important biomarker in breast oncology. Most guidelines set a positive expression threshold of 1% staining in immunohistochemistry (IHC) to define ER positivity. However, different expression levels may be associated with diverse degrees of sensitivity to endocrine therapy as ER expression may impact breast cancer molecular biology as a continuous variable. ER-lo tumors, defined as those with 1-10% ER expression, represent a relatively small subgroup of breast cancer patients, with an estimated prevalence of 2-7%. These tumors are similar to ERneg disease in their molecular landscape, clinicopathological characteristics, prognosis, and response to therapy. Nevertheless, a proportion may retain some degree of ER signaling dependency, and the possibility of responding to some degree to endocrine therapy cannot be completely ruled out. This review article discusses the most important considerations regarding the definition of ER positivity, pathology assessment, prognosis, and therapeutic implication of ERlo breast cancer from the medical oncology perspective.

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“…At present, IS detection is not widespread in clinical practice for economic reasons, and surrogate subtype identification through IHC techniques assessing HR, HER2, and Ki67 levels guides therapeutic choices ( 29 ). In this case, the absence of ER and the low levels of PR, along with the relapse under an AI, pointed toward the presence of an endocrine-resistant tumor with a potential triple-negative breast cancer (TNBC)-like behavior, for which upfront CT might have been a viable therapeutic option ( 30 – 32 ). In this perspective, IS detection gave us the possibility to more properly assess the biologic nature of the disease.…”

Section: Discussionmentioning

confidence: 95%

Intrinsic subtypes and therapeutic decision-making in hormone receptor-positive/HER2-negative metastatic breast cancer with visceral crisis: A case report

Schettini

Seguí²,

Conte³

et al. 2022

Front. Oncol.

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BackgroundCDK4/6 inhibitors (CDKi), namely, palbociclib, ribociclib, and abemaciclib, combined with either an aromatase inhibitor (AI) or fulvestrant are the standard first/second line for hormone receptor-positive(HR+)/HER2-negative(neg) metastatic breast cancer (MBC). However, the choice of one specific CDKi is arbitrary and based on the physician’s experience with the drug, toxicity profile, and patient’s preferences, whereas biomarkers for optimal patient selection have not been established so far. Moreover, upfront chemotherapy is still recommended in case of clinical presentation with visceral crisis, despite no evidence of superior benefit for chemotherapy regimens against CDKi-based regimens. Recent correlative biomarker analyses from pivotal trials of palbociclib and ribociclib showed that HR+/HER2-neg MBC might respond differently according to the molecular intrinsic subtype, with Luminal A and B tumors being sensitive to both CDKi, Basal-like being insensitive to endocrine therapy, irrespective of CDKi, and HER2-enriched tumors showing a benefit only with ribociclib-based therapy.Clinical caseWe hereby present a paradigmatic clinical case of a woman affected by a relapsed HR+/HER2-neg MBC with bone and nodal lesions, presenting with a visceral crisis in the form of lymphangitis carcinomatosis and diagnosed with a molecularly HER2-enriched tumor, successfully treated with upfront ribociclib + fulvestrant. The patient experienced a complete symptomatic and radiologic remission of the lymphangitis with a partial response as best response, according to RECIST 1.1 criteria. The progression-free survival (PFS) was of 20 months, in line with the median PFS observed in the ribociclib + fulvestrant pivotal trial, where, however, patients with visceral crisis had been excluded.ConclusionsThis clinical case confirms in the real-world setting that non-luminal subtypes can be found in HR+/HER2-neg disease and may have potential therapeutic implications in the metastatic setting. It also questions the recommendation of upfront chemotherapy in the case of a visceral crisis in the era of CDKi-based regimens. These issues merit further evaluation in prospective and larger studies.

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Impact of low versus negative estrogen/progesterone receptor status on clinico-pathologic characteristics and survival outcomes in HER2-negative breast cancer

Cited by 29 publications

References 36 publications

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Clinical implication of low estrogen receptor (ER-low) expression in breast cancer

Intrinsic subtypes and therapeutic decision-making in hormone receptor-positive/HER2-negative metastatic breast cancer with visceral crisis: A case report

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