HER2+ Early Breast Cancer: From Escalation via Targeted and Post-Neoadjuvant Treatment to De-Escalation Open Access

HER2+ disease accounts for 15–20% of breast cancer cases [1]. Early studies indicated that women with HER2+ early breast cancer (eBC) were at a higher risk of recurrence and had worse survival than those with HER2– disease [2]. For decades, chemotherapy (CTx) involving anthracyclines, frequently combined with taxanes, was a standard treatment for HER2+ and HER2–eBC. Over past 20 years, better understanding of biology and subsequent introduction of targeted therapies has dramatically changed the paradigm for the management of eBC and resulted in improved survival and reduced mortality, especially in HER2+ disease [3].

Discovery of HER2/neu proto-oncogene in early 1980s laid a foundation for development of HER2-targeting therapeutics. Trastuzumab (Herceptin^®, H), a monoclonal antibody that binds to HER2 receptors, was approved by FDA in 1998 as the first targeted therapy for HER2-positive metastatic breast cancer (mBC). Since then, several landmark clinical trials demonstrated a significant benefit of trastuzumab therapy in eBC in terms of reduced risk of recurrence and improved survival. The HERA trial (NCT00045032) was the first trial to show enhanced survival after adjuvant trastuzumab in node-positive or high-risk (≥1 cm) node-negative patients. The trial compared 1 and 2 years of H following standard CTx (predominantly anthracyclines) versus observation; H resulted in 8.4% improvement in 2-year and 6–8% improvement in 10-year disease-free survival (DFS), and 6.5–6.6% improvement in 10-year overall survival (OS, see Table 1) [4, 5]. Based on these results, trastuzumab gained FDA approval in 2006 for adjuvant treatment of HER2+, high-risk node-negative or node-positive eBC, following anthracycline-based therapy and became a corner stone therapy recommended by national and international guidelines (see Fig. 1). Subsequent adjuvant trials, NSABP B-31 (NCT00004067) and NCCTG N9831 (NCT00005970), demonstrated a survival benefit of H combined with paclitaxel (Pac) following anthracyclines versus Pac in terms of substantially reduced relative risk of DFS event (by 40%) or death (by 37%) [6].

Despite these remarkable benefits, combination of H with anthracyclines also raised concerns about increased rates of left ventricular dysfunction and congestive heart failure. Therefore, further trials explored alternative regiments to reduce cardiac toxicity. For example, BCIRG 006 trial (NCT00021255) compared standard adjuvant anthracycline-taxane with or without H versus docetaxel, carboplatin, and H [7]. Addition of H to taxane or anthracycline reduced the risk of recurrence (by 33% and 39%, respectively) or death (34% and 42%) versus CTx-only arm. In 2008, FDA approved both the docetaxel and carboplatin combined with H regimen and doxorubicin and cyclophosphamide followed by docetaxel and H regimen for the adjuvant treatment of eBC. Importantly, BCIRG 006 trial did not demonstrate a significant difference in DFS or OS between the anthracycline- and taxane-based treatments containing H, although worse toxicity profile (more cardiotoxicity and acute leukemia) was observed in the anthracycline-containing arm. Therefore, for the first time, eBC patients gained access in routine clinical practice to efficacious anthracycline-free treatment with a better safety profile.

In parallel to adjuvant setting, investigators have been testing H-containing neoadjuvant approaches. Neoadjuvant therapy (NAT) allows a direct evaluation of treatment efficacy, and it can result in tumor shrinkage, potentially increasing the chance of breast-conserving surgery. Buzdar et al. [8] were among the first to report the increased rates of pathologic complete response (pCR) after addition of H to Pac followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) in patients with stage II–IIIA eBC (65.2% vs. 26%). Subsequently, the NOAH trial (ISRCTN86043495) investigated neoadjuvant doxorubicin and Pac, followed by Pac, and then by cyclophosphamide, methotrexate, and 5-fluorouracilin with or without H in locally advanced or inflammatory eBC. Addition of H substantially improved pCR (42% vs. 23%) and 5-year event-free survival (EFS, 58% vs. 43%) versus CTx-only treatment [9, 10]. Importantly, NOAH was among the first trials to provide evidence for improved survival in patients with pCR following H treatment (5-year EFS: 86.5% in patients with pCR vs. 54.8% in the entire trial) [11]. These results corroborated the prior findings from the TECHNO trial (NCT00795899) investigating epirubicin and cyclophosphamide followed by Pac and H (3-year DFS: 88% vs. 73%, and 3-year OS: 96% vs. 86% in patients with and without pCR, respectively) [12]. Given the totality of evidence for improved survival, H in combination with CTx in either neoadjuvant or adjuvant setting has been incorporated into several national and international guidelines and has become a new standard of care for HER2+ eBC.

Despite the benefits of H, there are several escape mechanisms limiting its efficacy, including insufficient inhibition of HER2 receptor or induction of alterative signaling pathways. A potential solution to this problem was HER2 blockade with concomitant use of two or more HER2-targeting agents which was shown to induce improved antitumor efficacy compared to single-agent approaches [13]. Pertuzumab was another type HER2-directed therapy investigated in eBC in combination with H. Pertuzumab (P) is an anti-HER2 antibody that targets subdomain II (as opposite to H which binds subdomain IV) thus preventing HER2 dimerization with HER3. While its inhibitory effect on signal transduction downstream from HER2 is less pronounced than that of H, concomitant use of both anti-HER2 antibodies results in the synergistic impact in decrease of breast cancer cell survival [14]. Neoadjuvant NeoSphere trial (NCT00545688) was the first trial to investigate H + P combination in eBC. This four-arm trial demonstrated 45.8% pCR rate after dual HER2 blockade+docetaxel compared to 29% and 24% in CTx combined with either H or P, and 16.8%. in patients who received H + P without CTx [15]. The results on pCR obtained within the NeoSphere trial led to an accelerated approval of neoadjuvant H + P + docetaxel in 2013. 5-year progression-free survival rates were only non-significant higher in the H + P arm (86% in H + P, 81% in H, 73% in P, and 73% in CTx-free H + P arm), although the trial was not supported for formal survival analysis [16]. Of note, pCR was associated with improved survival (85% vs. 76% in patients without pCR) [16]. Data from the adjuvant setting confirmed the beneficial effect on survival following double anti-HER2 therapy involving P. The APHINITY trial demonstrated a statistically significant improvement in 3-year iDFS after addition of P to H + standard adjuvant CTx (94.1% vs. 93.2%), with the highest benefit in node-positive eBC (92.0% vs. 90.2%) [17]. Survival analysis at 8 years confirmed a sustained iDFS benefit from addition of P (88.4% vs. 85.8%) which again was driven by its efficacy in the node-positive cohort (86.1% vs. 81.2%) [18]. A trend toward improved 8-year OS was observed in P arm (92.7% vs. 92.0% in placebo arm; 91.1% vs. 89.2% in node-positive cohort), although survival data were still immature. In 2017, the FDA granted approval for adjuvant use of P in patients at a high risk of recurrence and converted the previously granted accelerated approval for the neoadjuvant P to full approval. Nevertheless, due to a lack of direct comparison between adjuvant and neoadjuvant H + P regimens, it remains unclear whether H + P should be continued in patients with pCR and node-positive disease at baseline. There are only a few retrospective data analyses which support a higher efficacy of such strategy [19].

Recent years saw a continuous effort in improving the outcomes of HER2+ eBC by developing new anti-HER2 agents or modification of the existing drugs to increase their anti-cancer efficacy. Antibody-drug conjugates (ADCs), composed of an antibody linked to cytotoxic agent, have been shown to prolong survival in mBC. Trastuzumab emtansine (T-DM1) is an HER2-targeted ADC which was investigated in the KATHERINE trial (NCT01772472), addressing the need for better adjuvant approaches to manage a higher risk of recurrence in patients with residual disease after NAT. Most of the patients in the trial had locally advanced tumors before NAT and all were treated by at least 16 weeks of taxane-containing therapy plus H (18% of included patients additionally received P, current standard of care). The trial has demonstrated that a T-DM1, compared to H alone, has reduced the risk of invasive disease recurrence by 50%, (3-year iDFS rates: 88.3% vs. 77%) [20]. Results of the KATHERINE trial led to T-DM1 approval by FDA in 2019 and established T-DM1 as the new standard of care therapy for patients with residual disease after NAT (i.e., in the post-neoadjuvant setting). However, a concern remains about the use of single HER2 blockade with only H as a comparator, which is suboptimal at least in patients with node-positive disease.

T-DM1 was also tested in combination with P following the anthracycline in the adjuvant KAITLIN trial (NCT01966471); however, it failed to demonstrate a survival benefit over H + P + taxane in patients with a high-risk of recurrence (3-year iDFS: 93.1% vs. 94.2%) [21]. Trastuzumab deruxtecan (T-DXd) is a new generation ADC consisting of highly cytotoxic, cell membrane-permeable payload able to target neighbor cells via bystander effect and connected to the antibody with a cleavable linker which increases the stability in plasma [22]. T-DXd is indicated for treatment of HER2+ and HER2–low mBC and is now being tested in the neoadjuvant (e.g., DESTINY-Breast11, NCT05113251; ADAPT-HER2-IV, NCT05704829) and post-neoadjuvant setting (DESTINY-Breast05, NCT04622319).

Personalized medicine aims to tailor the treatment, specifically for a given patient. A significant obstacle for adoption of this concept is differentiation between patients for whom the standard therapy may be insufficient from those who are overtreated and who could benefit equally well with less toxic regimens. Therefore, a continuous effort over the last years has been made to optimize treatments for eBC by investigating different escalation and de-escalation approaches.

Early approaches for therapy escalation assumed that prolongation of treatment could result in improved survival. For example, HERA trial compared 1- and 2-year H therapy durations; however, it found no DFS benefit from treatment prolongation [5]. Still, available evidence suggests that survival can be prolonged with therapy extension by switching to a different HER2-targeted therapy. This was demonstrated in the ExteNET trial, demonstrating a small but notable improvement in iDFS after 1-year neratinib therapy after standard 1-year course of H, especially in patients with HR + disease, ≥4 positive lymph nodes, or in those who initiated neratinib within 1 year after finishing H treatment [23, 24]. However, the trial did not demonstrate a beneficial effect of pCR versus non-pCR on survival (5-year iDFS: 84% and 85% following neratinib, and 74% and 78% in the placebo arm) [25]. Furthermore, lack of P or T-DM1 use in the adjuvant treatment in the ExteNET trial precludes the comparison between different possible scenarios in the high-risk (e.g., node-positive) disease.

Several meta-analyses demonstrated non-pCR associates with worse long-term outcomes which stresses the need for new therapeutic options [26‒29]. Since the KATHERINE trial, the post-neoadjuvant setting has been incorporated into clinical practice to specifically select patients with residual disease at surgery for treatment escalation with T-DM1. This setting not only offers an opportunity to improve survival in patients at the highest risk of recurrence but also avoids at least surgical overtreatment in patients with pCR. However, OS benefit remains to be elucidated due to short follow-up of the KATHERINE trial. Moreover, further studies are urgently needed given the significantly better OS in the node-positive cohort in the APHINITY and in high-risk stage II–III HR + patients in the ExteNET adjuvant trials, respectively, in the exploratory analyses after longer follow-up.

Several adjuvant studies explored shorter durations of H treatment, however, with mixed results. For instance, a non-inferiority to standard 1-year H treatment was shown in the PERSEPHONE trial (NCT00712140) investigating 6-month H therapy and in the SOLD trial (NCT00593697) testing only 9-week approach [30, 31]. In contrast, other trials failed to show non-inferiority of 6-month (PHARE trial, NCT00381901) or 9-week H (Short-HER trial, NCT00629278) versus standard 1-year therapy duration [32, 33]. Meta-analysis performed by Chen et al. [34] demonstrated that 1-year H confers a substantial DFS benefit compared with shorter schedules. However, 6-month H was non-inferior to 12-month therapy in meta-analysis by Earl et al. [35].

Other therapy de-escalation approaches focused on reducing the intensity of CTx or omitting it altogether. Initial efforts in this area tested the substitution of anthracyclines by less toxic chemotherapeutic agents. Single arm phase II study APT (NCT00542451) in stage I HER2+ eBC investigating adjuvant Pac+H demonstrated 3-year iDFS of 98.7% with only 0.5% rate of heart failure [36]. This remarkable survival rate combined with an excellent safety profile led to adoption of Pac+H into standard of care in small, node-negative disease; 10-year survival analysis (iDFS rate: 91.3%, OS: 94.3%) supported this decision [37]. Omission of anthracyclines was also tested in stage II–III eBC in the TRAIN-2 trial (NCT01996267) which randomized patients to neoadjuvant 5-FEC followed by Pac, carboplatin, and H + P or the same regimen without FEC. Resulting pCR rates were similarly high in the anthracycline-containing and anthracycline-free arms (67% and 68%) as were the 3-year EFS (92.7% and 93.6%) and OS rates (97.7% and 98.2%) [38, 39]. However, use of anthracyclines was associated with a higher frequency of febrile neutropenia, cardiac toxicity, and acute leukemia [38, 39]. The TRYPHAENA (NCT00976989) trial investigating neoadjuvant H + P concomitantly with FEC and then with docetaxel versus FEC followed by docetaxel and H + P versus docetaxel+carboplatin+H+P corroborated the results of a high efficacy of anthracycline-free approaches in terms of pCR (61.6% vs. 57.3% vs. 66.2%) and 3-year DFS (87% vs. 88% vs. 90%) [40, 41].

Targeted delivery of potent cytotoxic agents offered by ADC can be considered as a de-escalation approach minimizing the toxicity associated with standard systemic CTx. As mentioned above, the KATHERINE trial established T-DM1 as the preferred post-neoadjuvant treatment; however, little progress has been made since then toward further incorporation of ADCs as less toxic alternative to CTx. For example, although T-DM1 demonstrated a 3-year iDFS rate of 97.8% in stage I eBC in the ATEMPT trial (NCT01853748), its safety profile was not improved compared to H + Pac [42]. In the neoadjuvant setting, double HER2 blockade with T-DM1+P showed inferior pCR rates compared to standard docetaxel+carboplatin+H+P in the KRISTINE trial (NCT02131064; 44.4% vs. 55.7%), lower 3-year EFS (85.3% vs. 94.2%) but comparable iDFS (93.0% and 92.0%) [43, 44]. pCR was associated with improved survival and with no differences between the T-DM1+P and H + P therapy (3-year iDFS: 96.7% and 97.5%) [44]. Safety analysis demonstrated a lower incidence of ≥3 adverse events during the NAT with T-DM1; however, T-DM1 was associated with worse safety profile and more frequent treatment discontinuations in adjuvant phase [44]. Conversely, neoadjuvant PREDIX HER2 trial (NCT02568839) reported a similar efficacy of T-DM1 versus docetaxel+H+P in terms of pCR (43.9% vs. 45.5%) and survival [45, 46].

CTx-free approaches have been investigated in several trials in HER2+ eBC and indicate that a subset of patients might benefit from such de-escalation. The NeoSphere was the first trial to investigate neoadjuvant CTx-free treatment, with 16.8% pCR rate after H + P [15]. Similarly, the WSG-ADAPT-HR-/HER2+ trial (NCT01817452) demonstrated a clinically meaningful pCR rates of 36.3% after CTx-free NAT involving H + P (compared to 90.5% after concomitant Pac) [47]. Remarkably, despite a difference in pCR, CTx-free NAT did not result in a lower survival (87% vs. 98%). Furthermore, patients with pCR after CTx-free NAT had a similar survival irrespectively of further CTx use [48]. In the HR + disease, the WSG-ADAPT-HR+/HER2+ trial (NCT01745965) randomized patients to T-DM1 with or without ET or to H with ET, resulting in pCR rates of 41.5%, 41.0%, and 15.1%, respectively [49]. Despite a higher efficacy of T-DM1 versus H, survival was similar across all arms due to mandatory conventional CTx after non-pCR [50]. Overall, results of the WSG-ADAPT trials suggest that conventional CTx can be avoided in a significant proportion of patients. Furthermore, the WSG-TP-II trial (NCT03272477) showed an increased pCR following Pac versus ET and H + P (56.4% vs. 23.7%) [51]. A markedly lower sensitivity of HR+/HER2+ tumors to CTx-free NAT was investigated in the PerELISA trial (NCT02411344) in which stage II–III eBC patients received a 2-week course of letrozole followed by Ki67 measurement in core biopsies. Molecular responders (>20% Ki67 signal reduction relative to diagnostic core biopsy) continued letrozole and additionally received H + P while non-responders discontinued ET and underwent Pac, H + P treatment. This response-guided approach resulted in pCR rate of 20.5% in responders and 81.3% in non-responders [52]. A similar response-adapted strategy was used in the PHERGain trial (NCT03161353) which randomized patients to H + P with or without docetaxel and carboplatin. Patients in the CTx-free arm who had ¹⁸F-FDG-PET metabolic response after 6 weeks continued the treatment, while non-responders received additional CTx, the corresponding pCR rates were 37.9% and 25.9% [53], respectively. Subsequently, CTx-free adjuvant treatment (H + P) was administered to patients with pCR, while those with non-pCR additionally received CTx. 3-year iDFS in patients who were initially randomized to H + P and then underwent response-guided therapy was 95.4% (98.8% in those who never received CTx) and 98.3% in patients on continuous neoadjuvant CTx+H+P therapy followed by adjuvant H + P [54]. Another marker of early response is a low cellularity in on treatment biopsies (alone or in combination with Ki67 decrease or other cellular markers) which has been shown to be associated with pCR or survival in several trials (PAMELA [NCT01973660], WSG-TP-II [NCT03272477], WSG-ADAPT-HR+/HER2+, and WSG-ADAPT-HER2+/HR- [47, 49, 55, 56]). An important advantage of this approach compared to PET-based methods is a higher feasibility for clinical use since it involves standard pathological analyses.

Furthermore, there is a significant interest in the development of gene expression-based tools for prediction of therapy response and survival. For instance, HER2DX score integrates clinical characteristics with gene expression signatures related to immune response, proliferation, luminal differentiation, and HER2 amplicon. In the analysis of several trials in HER2+ eBC, HER2DX score was found to predict pCR, cancer recurrence, and was shown to identify patients who could benefit from dual HER2 blockade [57‒59].

Continuous research over the last two decades has gradually improved the survival of patients with HER2+ disease, a BC subtype historically associated with a particularly poor prognosis. Today, modern anti-HER2 agents may even allow omission of CTx without compromising the outcome in approximately a third of selected patients with eBC. Nevertheless, some tumors do not sufficiently respond to therapy and relapse. Ongoing efforts to improve patient outcomes include the development of new ADCs, including those targeting HER3, anti-HER2 vaccines, or use of immunotherapy. Moreover, we embraced the molecular heterogeneity of HER2+ eBC and the current research focuses on identification of new prognostic and predictive biomarkers. Analysis of gene expression, immune cell signatures, and circulating tumor DNA, among other biomarkers, is poised to pave the way toward the development of truly personalized therapy.

M.G. received consulting fees from AstraZeneca and travel support from Daiichi Sankyo, all outside of the submitted work. O.G. received consulting fees from Celgene, Genomic Health/Exact Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen, Pierre Fabre, Gilead, and Molecular Health; honoraria from Genomic Health/Exact Sciences, Roche, Celgene, Pfizer, Novartis, NanoString Technologies, and AstraZeneca; payment for expert testimony from Genomic Health; and travel support from Roche, all outside of the submitted work; and co-director position at West German Study Group.

Not applicable.

M.G. wrote the first draft of the manuscript. M.G. and O.G. critically reviewed the final version of the manuscript and accepted responsibility to submit for publication.