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. Author manuscript; available in PMC: 2021 Jul 30.
Published in final edited form as: Clin Cancer Res. 2020 Feb 11;26(12):2783–2788. doi: 10.1158/1078-0432.CCR-19-2612

What is the real impact of estrogen receptor status on the prognosis and treatment of HER2-positive early breast cancer?

Mariana Brandão 1, Rafael Caparica 1, Luca Malorni 2, Aleix Prat 3,4, Lisa A Carey 5, Martine Piccart-Gebhart 1
PMCID: PMC8324078  NIHMSID: NIHMS1718756  PMID: 32046997

Abstract

HER2+ early breast cancer is a heterogeneous disease, comprising all the intrinsic breast cancer subtypes. The only biomarker available nowadays for anti-HER2 treatment selection is HER2 status itself, but estrogen receptor (ER) status is emerging as a robust predictive marker within HER2+ disease. In this Perspective, we discuss the biological and clinical differences between patients with HER2+/ER positive (ER+) disease versus those with HER2+/ER negative (ER-neg) tumors, namely short- and long-term (>5 years after diagnosis) prognosis, response to neoadjuvant treatment and benefit from adjuvant anti-HER2 targeted therapies. We also address other possible biomarkers to be used for patient selection in future clinical trials, like gene signatures, PAM50 subtypes, tumor-infiltrating lymphocytes, PIK3CA mutations, and changes in Ki67 score during treatment and discuss their limitations. Finally, we suggest new clinical trial designs that can have an impact on clinical practice, aiming to test treatment de-escalation separately for patients with HER2+/ER+ and HER2+/ER-neg tumors. We also propose an integrated classification of HER2+ disease, comprising DNA, RNA, protein expression and microenvironment characteristics, in order to identify those tumors that are truly “HER2-addicted” and may benefit the most from anti-HER2 treatment.

Keywords: breast cancer, HER2, Biomarkers, estrogen receptor

Perspective

It is well-known that HER2+ breast cancer is a heterogeneous disease (1,2). Besides HER2 status itself, there are no validated biomarkers to identify patients likely to benefit from anti-HER2 treatments (3). It has been proposed, however, that the expression of the estrogen receptor (ER) drives variable degrees of benefit from existing anti-HER2 treatment strategies. An increasing number of trials are being developed targeting specifically HER2+/ER-positive (ER+) or HER2+/ER-negative (ER-neg) early breast cancer (EBC) and we believe that, in the future, these may be regarded as distinct diseases or we may need additional tools to identify the varying biology within HER2+ disease that is represented by ER status.

Biological differences

Distinct biological characteristics may justify the different clinical behavior observed in HER2+ EBC according to ER status. The ER- and the HER2-pathways drive breast cancer proliferation by a complex interaction of cellular signaling processes (4). Due to the intracellular crosstalk between HER2 and ER, treatments interfering with one of the two pathways can have an effect on the other, with reactivation of ER-signaling being a known mechanism of resistance to anti-HER2 agents in HER2+/ER+ breast cancer (5).

The distribution of intrinsic (PAM50) breast cancer subtypes within HER2+ tumors also differs according to ER status (6): around 75% of HER2+/ER-neg tumors and 30% of HER2+/ER+ are “HER2-Enriched”, which is the subtype associated with HER2/EGFR-pathway activation (2), high proliferation rates, and an immune-activated stroma with elevated tumor-infiltrating lymphocytes (TILs) concentrations (Figure 1). On the other hand, around 70% of HER2+/ER+ tumors are luminal A/B, which are ER-dependent tumors, with low HER2/EGFR-pathway activation and a high rate of PIK3CA mutations (1), that are associated with lower response to anti-HER2 treatment (7).

Figure 1 – Current and future classification of HER2+ disease.

Figure 1 –

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Legend: HER2+ tumors can be divided between estrogen receptor (ER)-positive and ER-negative subgroups, according to the immunohistochemical expression of ER. Yet, at the molecular level, these tumors can be divided into the four molecular subtypes (luminal A, luminal B, HER2-enriched and basal-like), showing different molecular alterations, cell pathways activation and immune microenvironment. This leads to different responses to anti-HER2 treatment, as well to chemotherapy and endocrine therapy.

ER: estrogen receptor; HER2-E: HER2-enriched molecular subtype; LumA: luminal A molecular subtype; LumB: luminal B molecular subtype; mut: mutation; TILs: tumor-infiltrating lymphocytes; WT: wild-type.

Differences in prognosis between HER2+/ER+ and HER2+/ER-neg EBC in the “trastuzumab era”

In the first 5 years after diagnosis, HER2+/ER-neg patients have worse survival compared to the HER2+/ER+ group. Among 42,887 patients treated between 2010–2015, 5-year overall survival (OS) rates were 88.2% in HER2+/ER+ vs. 83.9% in HER2+/ER-neg subgroup (p<0.001) (8). Yet, after 5 years, recurrence risk lowers among HER2+/ER-neg patients, but is maintained among those with HER2+/ER+ tumors (9–11). This leads to similar long-term prognosis: in the HERA trial, 12-year OS in the trastuzumab arms was 81% in the HER2+/ER+ and 78%−79% in the HER2+/ER-neg subgroup (9).

On the other hand, achievement of a pathological complete response (pCR) after neoadjuvant treatment is a prognostic factor in both groups, but it has a stronger impact on event-free survival (EFS) in the HER2+/ER-neg (hazard ratio [HR] 0.25) compared to the HER2+/ER+ subgroup (HR 0.58) (12). However, overall median follow-up for EFS in this meta-analysis was just 5.4 years, thus the prognostic impact of pCR on late recurrences is currently unknown.

Is ER status predictive of treatment benefit?

It is well-documented that HER2+/ER-neg patients treated with chemotherapy and dual anti-HER2 therapy present higher pCR rates (61%−91%) compared to patients with HER2+/ER+ EBC (26%−56%) (13–20); and, compared with HER2+/ER+ tumors, HER2+/ER-neg tumors have consistently demonstrated greater increases in pCR rates with dual anti-HER2 therapy plus chemotherapy compared with chemotherapy/trastuzumab alone (13,18–20). Nonetheless, duration of anti-HER2 treatment seems to matter in HER2+/ER+ EBC: in TBCRC023, increasing treatment length with trastuzumab/lapatinib and letrozole from 12 to 24 weeks led to an increase in pCR rates from 9% to 33%, whereas no significant difference was observed in HER2+/ER-neg tumors (21). This suggests that in HER2+/ER+ tumors, in the absence of chemotherapy, prolonged inhibition of the HER2 and ER pathways may be necessary not only to decrease proliferation, but to induce apoptosis as well. Yet, adding concomitant endocrine therapy (ET) to anti-HER2 therapy and/or chemotherapy did not yield any advantage in the NSABP B-52 or ADAPT HER2+/HR+ studies (22,23). This is intriguing, as one would expect that the ER/HER2 pathways-blockade would suppress their crosstalk and lead to higher tumor response.

On the opposite end of the spectrum, the high chemo-sensitivity of HER2+/ER-neg tumors was demonstrated in the ADAPT HER2+/HR- study, in which the addition of paclitaxel to trastuzumab/pertuzumab increased pCR rates from 36% to 91% (17). Similarly, the KRISTINE trial showed a significantly higher pCR rate in this group with docetaxel/carboplatin plus trastuzumab/pertuzumab compared to T-DM1/pertuzumab (73% vs. 54%, respectively) (16).

In the adjuvant setting, HER2+/ER+ and HER2+/ER-neg subgroups have a similar degree of proportional risk reduction with trastuzumab (9,24,25). Yet, in contrast with the neoadjuvant setting, duration of adjuvant trastuzumab treatment might matter more for HER2+/ER-neg EBC: in a recent meta-analysis, patients receiving 9 weeks to 6 months of trastuzumab had worse EFS compared to patients treated for 12 months (26). Therefore, in HER2+/ER-neg disease, longer trastuzumab treatment is probably more effective than a shorter course. However, the trials included in this meta-analysis had a median follow-up of less than 5 years, so long-term data on HER2+/ER+ patients are needed.

Challenging this idea, the ExteNET trial showed that sequential anti-HER2 blockade (summing two years of treatment) was beneficial for HER2+/ER+ patients, but not for HER2+/ER-neg patients (27). On the other hand, updated survival results from APHINITY show that early dual HER2-blockade with trastuzumab/pertuzumab has an effect both in HER2+/ER-neg and HER2+/ER+ diseases (28). Reasons for this difference may lie in these drugs’ mechanisms of action, timing of administration, and length of follow-up. After stopping adjuvant trastuzumab, HER2+/ER+ patients continue ET, but the single-blocking of the ER-pathway may lead to re-activation of the HER2-pathway on residual trastuzumab-resistant malignant cells (4). As neratinib was administered after trastuzumab, it may have prevented the re-activation of the HER2-pathway and, hence, benefited HER2+/ER+ patients, but not those with HER2+/ER-neg tumors. As neratinib irreversibly inhibits several HER-family members (EGFR, HER2, HER4), it may have prevented this cross-talk in a more effective way than administration of trastuzumab for 2 years (which only inhibits HER2) (9). In APHINITY, the early dual blockade has probably eliminated trastuzumab-resistant cells in part of the patients, but the benefit was seen later in HER2+/ER+ patients, has these tend to have later relapses, as compared to HER2+/ER-neg patients. .

Recently, the KATHERINE trial showed that in patients with residual disease after neoadjuvant treatment, 1 year of adjuvant T-DM1 was superior to trastuzumab, independently of ER status (29). It should be noted that this trial included selected high-risk patients, for whom suboptimal response to neoadjuvant trastuzumab could have influenced the benefit from a salvage treatment with a different anti-HER2 drug, potentially confounding the effect of baseline ER status.

How can we identify patients who benefit more or less from anti-HER2 treatment?

The biggest question nowadays is how to select patients for escalation/de-escalation approaches, maintaining or increasing pCR rates and survival, with minimal toxicity. Therefore, the quest for finding prognostic and predictive biomarkers has been intense (3). One attempt was to quantify gene expression levels of ESR1 and ERBB2, showing that high levels of ERBB2 (20,30–32) and low levels of ESR1 (31) are associated with higher pCR rates. Expression levels of genes involved in HER2- and ER-pathways were also combined in a predictive model in an analysis of the NSABP B-31 trial. Patients were classified into 3 groups: i) “high ESR1”/“low-intermediate ERBB2”: no benefit from trastuzumab (HR 1.58); ii) “low ESR1”/“low-intermediate ERBB2”: moderate benefit (HR 0.60); iii) “low-intermediate ESR1”/“high ERBB2”: large benefit (HR 0.28) (33). This 8-gene signature, showing no linear correlation between ERBB2 and ESR1 mRNA levels and benefit from adjuvant trastuzumab, was later validated in the N9831 and FB-7 trials (34,35). Nonetheless, these intriguing findings have not yet been tested in prospective studies or applied in the clinic.

Other biomarker studies focused on the correlation between PAM50 subtypes and benefit from anti-HER2 treatment. A consistent finding is that HER2-Enriched tumors present higher pCR rates (between 28%−72%) when treated with anti-HER2 therapies (with/without chemotherapy), compared to other subtypes (20,32,36,37), showing that HER2-Enriched subtype predicts sensitivity to anti-HER2 treatment. In fact, several studies show that ER status loses its association with pCR when subtype is taken into account, indicating that subtype captures most of the information displayed by ER status and also brings additional information (20,32,36,37). One important aspect to take into account when designing de-escalation trials is that HER2-Enriched subtype is also chemo-sensitive, with overall pCR rates in HER2+ disease of around 60% with vs. 30% without chemotherapy, respectively (20,32,36,37).

It has also been proposed that high scores of a gene expression-signature of loss-of-function of RB1 may identify HER2+ tumors more likely to respond to chemotherapy and this concept has been validated in HER2+/ER+ tumors using a refined 87 gene-signature (RBsig) (38,39). Moreover, higher TILs levels are associated with improved pCR rates and survival both in HER2+/ER-neg and HER2+/ER+ EBC (40,41), and evidence of immune activation by RNA-signatures is independently associated with higher pCR (20,31). It has also been demonstrated that high TIL levels (>75%) predicted benefit from adjuvant trastuzumab/pertuzumab vs. trastuzumab alone (42). Of note, TILs levels tend to be lower in HER2+/ER+ compared to HER2+/ER-neg tumors (40).

A decrease in Ki67 during neoadjuvant treatment is a surrogate for response and prognosis in HER2-negative/ER+ EBC, so its role is being evaluated in HER2+/ER+ disease (43). In ADAPT HER2+/HR+, patients with an early tumor response (Ki67 decrease≥30% or low-cellular tumor at 3 weeks) had a higher pCR rate compared to nonresponders (36% vs. 20%, respectively) (23). In the PerELISA trial, HER2+/ER+ patients with a Ki67 drop after 2 weeks of letrozole (molecular responders) continued on letrozole, and trastuzumab/pertuzumab were added for another 12 weeks. Nonresponders were switched to paclitaxel with trastuzumab/pertuzumab. The pCR rate was 21% among molecular responders, but even more remarkable was the 81% pCR rate among nonresponders (44). Even though the correlation between an early Ki67 drop and long-term survival is not yet validated in patients with HER2+ tumors, it could become a biomarker for selecting patients with HER2+/ER+ who do not respond to ET and would be candidates to chemotherapy, given the impressive pCR rate achieved in this subgroup.

Thus, a dilemma for future clinical trials is how to select patients: should one be guided by HER2/ER immunohistochemistry status, by molecular subtype or by a combination of both? Based on current evidence, tumors with the highest anti-HER2 sensitivity are those HER2+ by immunohistochemistry/ISH and the PAM50 HER2-Enriched. Whether additional biomarkers will help identify higher anti-HER2 sensitivity is currently unknown, although TILs and PIK3CA mutations arise as promising candidates (Figure 2). Indeed, tumors with high HER2 amplification and an intact PI3K pathway are especially sensitive to HER2-targeted therapies (30). TILs could also potentially be used to select patients, but there are no standardized cut-points to define “high” vs. “low” TILs infiltration (45). Another question is if an early biopsy to assess Ki67 levels should be performed in HER2+/ER+ patients receiving neoadjuvant treatment. This is limited by Ki67 low reproducibility (46) and absence of validation as a surrogate for long-term survival benefit in HER2+ EBC.

Figure 2 – Combining biomarkers in HER2+ disease.

Figure 2 –

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Currently, protein expression assessed by immunohistochemistry is the standard method to classify breast cancer into different subtypes, according to tumor’s HER2 and estrogen receptors expression. However, an integrated classification of HER2-positive breast tumors, based on their DNA, RNA, protein expression, and microenvironment is needed to implement more precise and guided treatments and to identify those tumors “addicted” to the HER2 cellular pathway. Here, we propose a definition of “HER2-addicted” tumors that can be further refined in the future, as more data become available.

ER: estrogen receptor; HER2-E: HER2-enriched molecular subtype; PR: progesterone receptor; Rbsig: RB loss of function signature; WT: wild-type.

De-escalating strategies: a plea for separate trials according to ER status

Despite distinct biological and clinical characteristics between HER2+/ER-neg and HER2+/ER+ EBC, they are still treated similarly, except for ET. Nevertheless, different de-escalation strategies for HER2+ EBC might be explored according to ER status: a) to decrease anti-HER2 treatment duration; b) to avoid anthracyclines, and c) to design chemotherapy-free regimens.

As detailed before, a meta-analysis showed a worse outcome with a shorter treatment duration of adjuvant trastuzumab in patients with HER2+/ER-neg disease, but this comparison was non-significant in patients with HER2+/ER+ tumors. Moreover, in the PERSEPHONE trial (the only trial so far proving its non-inferiority hypothesis of 6 months vs. 1 year of trastuzumab), the HR for the comparison of the two strategies was very close to 1 in the HER2+/ER+ subgroup (HR 0.91; 95% confidence interval, 0.68–1.21) (47). Therefore, in patients with HER2+/ER+ tumors, a shorter duration of trastuzumab treatment may be seen as a safe option by some – nonetheless, due to the late relapse profile of these tumors, longer follow-up data are needed before adopting this strategy.

The APT trial (in which patients with ≤3 cm, node-negative tumors received 12 weeks of paclitaxel and 1 year of trastuzumab) showed a 7-year invasive-DFS of 94.6% for HER2+/ER+ disease and of 90.7% for HER2+/ER-neg disease, with just four distant recurrences (1%) (48). Thus, this treatment de-escalation seems very safe for patients with low-burden tumors. Given the high chemo-sensitivity of HER2+/ER-neg tumors, leading to a higher rate of pCR, a possible strategy for avoiding anthracyclines in patients with somewhat larger tumors would be to assess the tumor’s sensitivity upfront with neoadjuvant double HER2-blockade plus a taxane. The DeCrescendo trial will test this hypothesis in patients with cT1c-T2N0 HER2+/ER-neg tumors, who will receive 12 weeks of taxanes plus trastuzumab/pertuzumab. Those who achieve pCR will be spared from adjuvant anthracyclines and will only receive double HER2-blockade until completion of 1 year of treatment. The study is powered to test 3-year relapse-free survival (RFS) rate, with a narrow confidence interval, primarily in patients with PAM50 HER2-Enriched tumors and then in the overall population.

The reduced chemo-sensitivity of HER2+/ER+ EBC fuels the interest in alternative, targeted approaches without chemotherapy. One is the use of CDK4/6 inhibitors, which synergize with trastuzumab in HER2+/ER+ tumor models (49). In the small NA-PHER2 study, 20 weeks of palbociclib/ET/trastuzumab/pertuzumab provided a significant reduction in tumor proliferation, but led to a modest pCR rate of 27% (50). Long-term survival results and efficacy according to molecular subtypes are awaited. There are ongoing trials (PALTAN [NCT02907918]; TOUCH [NCT03644186]) exploring this approach. In particular, TOUCH is assessing RBsig (39) as a potential biomarker to identify HER2+/ER+ patients who could be spared from chemotherapy and treated with ET/anti-HER2/palbociclib. On the other hand, a recent joint analysis of neoadjuvant “chemotherapy-free” trials (SOLTI-PAMELA, TBCRC023/TBCRC006, and PerELISA) has shown that the combination of the HER2-Enriched subtype with a high mRNA expression of ERBB2 leads to the identification of a subgroup of patients exquisitely sensitive to double HER2-blockade – with pCR rates ranging from 44.5%−66.7% (51). Among HER2+/ER+ patients, only 32% were “HER2-Enriched/ERBB2-high”, whereas among the HER2+/ER-neg subgroup there were 68% of patients with this profile. Hence, as the HER2+/ER-neg subgroup is clearly enriched with these HER2-addicted tumors, one could envision a trial restricted to HER2+/ER-neg patients: they would be screened upfront and those with a HER2-enriched/ERBB2-high expression tumor would be proposed to receive neoadjuvant trastuzumab/pertuzumab only. Like in the DeCrescendo trial, patients achieving pCR would be spared of any adjuvant chemotherapy and the primary endpoint would be a high RFS rate with a narrow confidence interval.

Conclusion

Given the predictive value of ER status, it would be reasonable for the next wave of clinical trials to target separately HER2+/ER+ and HER2+/ER-neg patients. This would lead to a better tailoring of de-escalation treatment strategies, and hence to a greater chance of “success”. In addition, this could greatly reduce the morbidity and costs associated with the long and intense systemic regimens that patients with HER2+ tumors still receive, despite years of biomarker research. Thus, besides the use of ER status, we feel that an integrated classification of HER2+ tumors, based on their DNA, RNA, protein expression and immune microenvironment would also be useful for further treatment refinement in the future.

Statement of translational relevance.

HER2+ early breast cancer is a heterogeneous disease, in which estrogen receptor (ER) status is emerging as a robust predictive marker. This is related to the fact that the ER- and HER2-pathways drive breast cancer proliferation by a complex interaction of cellular signaling processes, including the sharing of intracellular effectors such as MAPK, PI3K and Src3. Thus, due to the crosstalk between HER2 and ER, treatments targeting one pathway can induce the activation of the other. This leads to a different clinical behavior of HER2+/ER+ disease as compared to HER2+/ER-neg early breast cancer. We discuss how the timing and sequencing of treatments, including anti-HER2 targeted therapy, can influence their benefit according to ER status. We also propose different de-escalation trial designs, with potential impact on clinical practice, separately for HER2+/ER+ and HER2+/ER-neg breast cancer, which should be regarded as distinctly different.

Acknowledgments

Funding

MB and RC acknowledge the support of Institut Jules Bordet, which funds their research fellowship.

Footnotes

Conflict of interest statement

MB: travel grant and speaker honoraria from Roche/GNE. RC: speaker honoraria from Boehringer Ingelheim, AstraZeneca and Janssen; travel grants from AstraZeneca and Pfizer. LM: advisory board for Pfizer and AstraZeneca; research grant from Pfizer. AP: part of an advisory board for NanoString Technologies; research grant from NanoString Technologies. LC: no conflict of interest. MP: consultancy for AstraZeneca, Lilly, MSD, Novartis, Odonate, Pfizer, Roche/GNE, Camel-IDS, Crescendo Biologics, Periphagen, Huya, Debiopharm, PharmaMar, G1 Therapeutics, Menarini, Seattle Genetics, Immunomedics, and Oncoloytics; board member of Radius. MB, RC and MP: research grants to their Institut: from Roche/GNE, Radius, AstraZeneca, Lilly, MSD, GSJ/Novartis, Synthon, Servier, and Pfizer.

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