Neoadjuvant treatment of HER2-positive breast cancer: should therapy differ based on hormone receptor status?
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ABSTRACT:
SUBMITTER: Harbeck N
PROVIDER: S-EPMC6048618 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Neoadjuvant treatment of HER2-positive breast cancer: should therapy differ based on hormone receptor status?
Therapeutic advances in medical oncology 20180711
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Project description:IntroductionThis project aimed to identify the frequency of a switch of hormone receptor (HR) and/or HER2 status after neoadjuvant chemotherapy (NAC) for early breast cancer.MethodsTumor samples from patients without pathological complete response (non-pCR) were evaluated. Pathological complete response (pCR) was defined as no invasive tumor in breast and lymph nodes (ypT0/is ypN0). HR and HER2 status determined before NAC was compared with the corresponding receptor status determined in the surgical specimen after NAC.Results245 consecutive patients with primary invasive breast cancer, treated with NAC with/without targeted therapy between January 1, 2016 and December 31, 2019, at the LMU Breast Center, Munich, Germany, were identified. In 128 patients (52%), surgery revealed non-pCR after completed NAC. In 35 cases (27%), a switch of either HR and/or HER2 status between the initial biopsy and the surgical specimen was detected. Twenty cases had a switch in HR status, while 15 cases had a switch in HER2 status.ConclusionIn a substantial number (27%) of non-pCR cases, a switch in biomarker status after completed neoadjuvant treatment was detected. These results are consistent with prior evidence. Yet, routine reevaluation of HR and HER2 status is not recommended in guidelines so far. Future research needs to address the impact of HR and HER2 status switch on therapy adaptation and on subsequent patient outcome. Particularly, in view of the recent therapy advances, it will be critical to evaluate whether individualization of treatment concepts based on the biology of the non-pCR specimens is preferable to the initial therapy concept based on the pathology at primary diagnosis.
| S-EPMC9851067 | biostudies-literature
Project description:BackgroundEndocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors.MethodsThis was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET.ResultsThirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis.ConclusionShort-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway.Clinical trial registryTrial registration number: NCT03219476.
| S-EPMC10795510 | biostudies-literature
Project description:Background. Endocrine resistant metastatic disease develops in ~20-25% of hormone-receptor positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods. This was a single arm, interventional phase II clinical trial evaluating 4 weeks (+/-1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥1 in IHC score following NET. Results. Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p=0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion . Short-term NET frequently and preferentially upregulates HER2 over other HER-family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Trial registration number: NCT03219476 Date of registration for prospectively registered trials: July 17, 2017.
| S-EPMC10104267 | biostudies-literature
Project description:PurposeWe do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer. The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ breast cancer.Experimental designIntrinsic subtype and clinicopathologic data were obtained from seven studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores [CES-C (chemo-sensitive), CES-U (uncertain), and CES-E (endocrine-sensitive)]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS).ResultsA total of 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U, and CES-E were identified in 60%, 23%, and 17% of the patients, respectively. High CES (i.e., CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted OR = 0.42; P = 0.016). A total of 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted HR, 0.174; P = 0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS HR of CES was 0.160 (P = 0.012).ConclusionsIn HER2+/HR+ breast cancer, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.
| S-EPMC8172481 | biostudies-literature
Project description:Single estrogen receptor (ER)+ and progesterone receptor (PR)+ tumors account for about10% of all breast cancers. However, the prognosis of these single hormone receptor-positive (HR+) tumor remains unclear. We aimed to investigate the characteristics of single HR+ breast tumors according to HER2 status in order to improve the treatment of patients with single HR+. Patients from the SEER program (2010-2016) were divided into ER+PR-, ER-PR+, ER+PR+ and ER-PR- molecular subtypes stratified by HER2 status. Overall survival (OS) and breast cancer-specific survival (BCSS) were compared by Kaplan-Meier curves after propensity score matching (PSM). A total of 203,406 patients were enrolled. Single ER+ and PR+ tumors account for 11.9% of the total population. For HER2- subtype, patients with ER+PR- (n = 16906 pairs) and ER-PR+ (n = 1395 pairs) had worse prognoses than those with ER+PR+ with hazard ratio (HR) and 95% confidence interval (CI) of 1.52 (1.41-1.64) and 2.25 (1.76-2.88) for OS; and 1.94 (1.76-2.14) and 2.57 (1.94-3.40) for BCSS, respectively; ER+PR- showed a better prognosis than ER-PR+ (n = 1394 pairs) and ER-PR- (n = 9626 pairs) with HR (95% CI) of 1.32 (1.06-1.65) and 1.44 (1.33-1.55) for OS, and 1.32 (1.03-1.69) and 1.46 (1.34-1.60) for BCSS, respectively; ER-PR+ had a similar prognosis relative to ER-PR- (n = 1395 pairs) after PSM. For HER2+ subtype, patients with ER-PR+, ER+PR-, and ER-PR- had similar OS and BCSS; ER+PR+ showed a similar prognosis compare with ER-PR+ (n = 535 pairs), but had better OS and BCSS than ER+PR- (n = 5376 pairs) and ER-PR- (n = 8143 pairs) after PSM. In addition, ER+PR+HER2+ showed similar OS and better BCSS compared with ER+PR+HER2- after PSM. In conclusion, single PR+ patients experienced poorer prognoses than single ER+ patients, and may be treated as ER-PR- patients in HER2- subtype. In HER2+ patients, both single ER+ and single PR+ cases showed similar prognoses compared with ER-PR- cases, and may be treated as ER-PR- patients.
| S-EPMC8165305 | biostudies-literature
Project description:Hormone receptor-positive/HER2-negative breast cancer (BC) is the most common subtype of BC and typically occurs as an early, operable disease. In patients receiving neoadjuvant chemotherapy (NACT), pathological complete response (pCR) is rare and multiple efforts have been made to predict disease recurrence. We developed a framework to predict pCR using clinicopathological characteristics widely available at diagnosis. The machine learning (ML) models were trained to predict pCR (n = 463), evaluated in an internal validation cohort (n = 109) and validated in an external validation cohort (n = 151). The best model was an Elastic Net, which achieved an area under the curve (AUC) of respectively 0.86 and 0.81. Our results highlight how simpler models using few input variables can be as valuable as more complex ML architectures. Our model is freely available and can be used to enhance the stratification of BC patients receiving NACT, providing a framework for the development of risk-adapted clinical trials.
| S-EPMC11799161 | biostudies-literature
Project description:BackgroundThe characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT.MethodsWe retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples.ResultsThe HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS.ConclusionsHER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.
| S-EPMC11261254 | biostudies-literature
Project description:Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments. The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.
| S-EPMC6314865 | biostudies-literature
Project description:Prognostic or predictive biomarkers in HER2-positive early breast cancer (EBC) may inform treatment optimization. The ADAPT HER2-positive/hormone receptor-positive phase II trial (NCT01779206) demonstrated pathological complete response (pCR) rates of ~40% following de-escalated treatment with 12 weeks neoadjuvant ado-trastuzumab emtansine (T-DM1) ± endocrine therapy. In this exploratory analysis, we evaluated potential early predictors of response to neoadjuvant therapy. The effects of PIK3CA mutations and immune (CD8 and PD-L1) and apoptotic markers (BCL2 and MCL1) on pCR rates were assessed, along with intrinsic BC subtypes. Immune response and pCR were lower in PIK3CA-mutated tumors compared with wildtype. Increased BCL2 at baseline in all patients and at Cycle 2 in the T-DM1 arms was associated with lower pCR. In the T-DM1 arms only, the HER2-enriched subtype was associated with increased pCR rate (54% vs. 28%). These findings support further prospective pCR-driven de-escalation studies in patients with HER2-positive EBC.
| S-EPMC8508505 | biostudies-literature
Project description:Approximately one quarter of patients with breast cancer demonstrate amplification of the human epidermal receptor type 2 (HER2) gene, the expression of which is associated with a relatively poor prognosis independent of other clinical and pathologic variables. Trastuzumab, a humanized recombinant monoclonal antibody specifically directed against the HER2 receptor, has been shown to be biologically active and of considerable clinical utility in HER2-positive breast cancer patients. Neoadjuvant chemotherapy has been used in breast cancer to downstage the tumor and increase the opportunity for breast-conserving surgery. Preoperative chemotherapy can also serve as an in vivo testing of chemotherapy sensitivity. Additionally, a pathologic complete response is usually a surrogate marker of disease-free survival. Following the successful use of trastuzumab in the metastatic and adjuvant settings, many clinical trials have recently reported the successful use of anti-HER2 therapy in combination with different chemotherapy regimens in the neoadjuvant setting with a significantly higher pathologic complete response. With the recent introduction of new anti-HER2 drugs, interest has shifted toward dual HER2 blockade. Two such studies were recently reported, both showing a significant advantage of dual anti-HER2 therapy using lapatinib or pertuzumab in addition to trastuzumab and chemotherapy. However, several key questions need to be investigated further, such as the preferred combination chemotherapy and the optimal duration of trastuzumab in patients who achieve a pathologic complete response following preoperative chemotherapy with trastuzumab. These issues and others are discussed in this review.
| S-EPMC3156251 | biostudies-literature