Treatment of small (T1mic, T1a, and T1b) node-negative HER2+ breast cancer: a review of current evidence for and against the use of anti-HER2 treatment regimens

Abstract

Introduction:

Since the advent of anti-HER2 therapies, evidence surrounding adjuvant treatment of small (T1mic, T1a, and T1b), node-negative, HER2-positive breast cancer (HER2+BC) has remained limited. Practices vary widely between institutions with little known regarding the added benefit of systemic therapy, including cytotoxic chemotherapy and HER2-directed treatments. Our group has set out to perform an extensive review of available literature on this topic.

Areas covered:

In this review, we examined HER2 biology, anti-HER therapies, outcome definitions, and available prospective and retrospective data surrounding the use of adjuvant therapy in those with small, node-negative, HER2+BC. For outcomes, we primarily explored breast cancer-specific survival (BCSS), invasive disease-free survival (iDFS), and overall survival (OS). We also investigated the incidence of adverse events with a particular focus on symptomatic and asymptomatic declines in left ventricular ejection fraction.

Expert opinion:

Retrospective data will likely be the main driver for future treatment decisions. Given what we know, high risk T1b and T1c subgroups derive measurable added benefit from HER2-guided combination therapies but it’s not clear whether these benefits outweigh known risks associated with this combination therapy. For tumors ≤0.5cm (T1mic and T1a), treatment remains highly controversial with limited evidence available through retrospective analysis that suggest over-treatment may be occurring.

1.0. Introduction to the biology and treatment of HER2+ breast cancer:

1.1. HER2 biology

Proto-oncoprotein HER2/neu (ERBB2) is a cell surface receptor that belongs to the epidermal growth factor receptor (EGFR) family of co-receptors. HER2 has an extracellular domain, transmembrane domain, and intracellular domain with tyrosine kinase activity. Activation of HER2 has been implicated in cell proliferation, suppression of apoptosis, and angiogenesis [1-3]. This occurs as a result of homo- or hetero-dimer formation with another HER2 receptor or another member of the receptor factor family (i.e. EGFR, HER3 and HER4), autophosphorylation, and activation of the tyrosine kinase domain. This action leads to downstream activation of several signaling pathways, including phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), phospholipase C γ, and protein kinase C [1-3]. The HER2 receptor is typically expressed on the surface of cells in the gastrointestinal tract, lungs, myocardium, endometrium, ovaries, and breasts [4-6]. HER2 gene amplification occurs in approximately 20-25% of breast cancers. As a result of this amplification, there is at least a 2-log increase in the number of HER2 receptors present on the cell surface, often to the point where HER2 receptor homodimers form spontaneously, allowing for autophosphorylation and activation [7]. This results in increased expression of genes important for cell growth, cell division, invasion, and metastases, leading to an aggressive form of breast cancer which, historically, has been associated with worsened survival outcomes both in the adjuvant and metastatic settings [8-11].

Expression of the HER2 protein on the surface of malignant cells is measured through use of immunohistochemistry (IHC) whereas HER2 gene amplification is measured through fluorescence in-situ hybridization (FISH) or chromogenic in-situ hybridization (CISH) [12]. Together, these results are used to determine HER2 positivity. Definitions regarding HER2 positivity have shifted through the decades, but joint guidelines through the College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO) have better refined this categorization to help guide treatment decisions and standardize clinical data [13].

1.2. Trastuzumab

The development of trastuzumab, the first humanized monoclonal antibody to target the extracellular domain of HER2, led to a paradigm shift in the management of HER2-positive breast cancer (HER2+BC) [14]. Trastuzumab was first approved by the Food and Drug Administration (FDA) in 1998 for use in metastatic HER2+BC in combination with chemotherapy following a pivotal trial by Slamon et al [15-17]. In 2006, trastuzumab was approved as adjuvant therapy in combination with conventional chemotherapy after interim analyses from four major clinical trials (NSABP B-31, NCCTG N9831, HERA, and BCIRG-006) found that one year of adjuvant trastuzumab added to standard adjuvant chemotherapy reduced the 3-year breast cancer recurrence risk by almost half and improved overall survival in patients with large or node-positive HER2+BC, regardless of the chemotherapy backbone used [18-20]. In 2008, a sub-group analysis from the HERA trial showed that, irrespective of nodal status, trastuzumab cumulatively reduced 3-year breast cancer recurrence rates by 36%, leading to trastuzumab’s approval for high risk HER2+BC [21-22]. High risk was defined at the time as those who either had a hormone-receptor negative (HR−) tumor, grade 2-3 disease, presence of axillary lymph node metastases, tumors >2cm in size regardless of lymph node status, or those aged <35 years old.

Given that progression can occur despite an initial treatment response to trastuzumab, a large effort has been made to better understand its downstream effects and the resistance pathways surrounding them. Studies have found that trastuzumab leads to the downregulation and internalization of HER2 receptors. It also elicits an antibody-mediated immune response, promotes G1 arrest, prevents DNA repair, and inhibits angiogenesis [23-26]. Cancer cells can become resistant to trastuzumab through a variety of mechanisms. Those tied to worsened clinical outcomes include the proteolytic formation of p95HER2 (truncated HER2 receptor that lacks an extracellular domain), overexpression of certain HER family receptors (allowing for further HER2 heterodimer activation), downregulation of PTEN (increases PI3K/Akt signaling), PIK3CA mutations (increases PI3K/Akt signaling), IGF-1R overexpression (increases MAPK/Akt signaling), c-MET overexpression (increases MAPK and PI3K/Akt signaling), cyclin E/CDK2 amplification (overrides p27kip1-induced G1 arrest), and Src overexpression (transmembrane HER family activation) [27-34].

Cardiotoxicity is a notable concern for those receiving trastuzumab therapy, whether alone or in combination with chemotherapy [8]. The cumulative incidence of asymptomatic and symptomatic cardiomyopathy observed in adjuvant trastuzumab trials has ranged from 3.8 to 11.2%, with concurrent anthracycline use contributing to the higher incidence rates observed [15]. The mechanism is thought to be related to the blunting of ErbB2 signaling, which is essential for cardiomyocyte growth and contractility [8, 35]. This impediment can stun cardiomyocytes, but this effect tends to be reversible in approximately 90% of patients following interruption of therapy [15, 18-20, 22]. Close monitoring is performed through either serial echocardiography or multigated acquisition (MUGA) scans before and during therapy. Cardiotoxicity is defined by the FDA as either symptomatic congestive heart failure (CHF), an asymptomatic drop in left ventricular ejection fraction (LVEF) by ≥16% from the pre-treatment level, or an asymptomatic drop in LVEF to <50% with an absolute decrease of ≥10% [14, 20, 22]. If cardiotoxicity is noted, trastuzumab is withheld for at least 4 weeks with concurrent initiation of a beta-blocker and an angiotensin-converting enzyme (ACE) inhibitor, followed by discontinuation of trastuzumab if recovery is not seen on follow up imaging. In contrast, if LVEF recovers to near baseline levels, trastuzumab can be safely resumed [36].

Since the approval of trastuzumab, additional anti-HER2 therapies have emerged, including other monoclonal antibodies (pertuzumab, margetuximab), antibody-drug conjugates (ado-trastuzumab emtansine, trastuzumab deruxtecan) and small molecule tyrosine kinase inhibitors with anti-HER2 properties (lapatinib, neratinib, tucatinib, afatinib). Below is a summary of some of the most widely used agents. A comprehensive review of these agents is outside of the scope of this article, but we highlighted pertinent trials and have referenced a few excellent resources for a more detailed overview [37-38].

1.3. Pertuzumab

Pertuzumab is a recombinant IgG1ϰ monoclonal antibody developed by Genentech that binds to the extracellular dimerization domain of HER2, thereby preventing HER2 from joining with other HER receptors [39-40]. Though initial phase 1/2 trials involving pertuzumab monotherapy were unimpressive, pertuzumab was found to be effective as a combination therapy with trastuzumab in order to provide dual anti-HER2 blockade [41-46]. In 2012, the FDA approved pertuzumab in the metastatic setting. This was based on the interim results of CLEOPATRA study, a phase 3 trial which randomized patients with metastatic HER2+BC to receive first line therapy with docetaxel and trastuzumab in combination with either pertuzumab or placebo. Interim results noted a significant increase in median progression-free survival (mPFS) from 12.4 months to 18.5 months (p<0.0001) [47]. Updated results after a median follow up of 99.9 months sustained these findings and showed a median overall survival (mOS) benefit of 57.1 months in the pertuzumab arm versus 40.8 months in the placebo arm [48].

Pertuzumab crossed into the neoadjuvant realm following the NeoSphere trial, which randomized HER2+BC patients with operable disease to one of four treatment arms including trastuzumab plus docetaxel, pertuzumab plus docetaxel, pertuzumab plus trastuzumab, and triple therapy (docetaxel, trastuzumab, pertuzumab) [49]. With the primary endpoint of pathological complete response (pCR), investigators found pCR rates were highest at 45.8% amongst those who received triple therapy (versus 29.0% with trastuzumab and docetaxel alone, p=0.0063). This was followed later by the TRYPHAENA study to assess cardiotoxicity with dual anti-HER2 therapy combined with chemotherapy [50]. Low incidence rates were seen among all treatment arms for both symptomatic (0-2.7%) and asymptomatic (3.9-5.6%) LVEF declines. The APHINITY trial then examined the utility of pertuzumab in the adjuvant setting by randomizing patients to either pertuzumab or placebo in addition to adjuvant trastuzumab and various chemotherapy regimens [51]. The primary endpoint of 3-year invasive disease-free survival (iDFS) was met by a very slim margin in the overall population (94.1% vs 93.2%, p=0.045), but on subgroup analysis, it was shown that the majority of benefit was derived from node-positive participants (3-year iDFS 92.0% vs 90.2%, p=0.02).

1.4. Antibody-drug conjugates

Ado-trastuzumab emtansine (T-DM1) is an antibody drug-conjugate which combines the humanized monoclonal antibody trastuzumab (T) with a cytotoxic microtubule inhibitor termed DM1 [52]. T-DM1 has been shown to provide a robust durable response rate and prolong overall survival in metastatic HER2+BC. These benefits were even found in pretreated metastatic HER2+ patients who had previously progressed on trastuzumab and taxane therapy, as reported in the phase 3 EMILIA trial (mOS 29.9 vs 25.9 months with lapatinib + capecitabine) and phase 3 TH3RESA trial (mOS 22.7 vs 15.8 months with chemotherapy of physician’s choice) [53-54].

T-DM1 later received FDA approval as adjuvant treatment for those with residual HER2+BC after neoadjuvant therapy. This approval was based on results from the phase 3 KATHERINE trial which demonstrated an improved 3-year iDFS of 88.3% after 14 cycles of T-DM1 versus 77.0% in patients treated with adjuvant trastuzumab monotherapy (HR 0.50, 95% CI 0.39-0.64, p<0.001) [55].

Although trastuzumab can confer a modest risk of cardiotoxicity, the EMILIA, TH3RESA, and KATHERINE trials demonstrated low cardiotoxicity rates with T-DM1 when compared to control arms containing lapatinib (1.6 vs 1.7%), physician’s choice (2 vs 2%), and trastuzumab (0.1 vs 0.6%) therapy [53, 55]. In the KATHERINE trial, administration of TDM-1 did, however, come with a higher rate of discontinuation compared to trastuzumab (18.0 vs 2.1%, respectively) along with a higher incidence of pneumonitis (2.6 vs 0.8%), ALT elevations (23.1 vs 5.7%), AST elevations (28.4% vs 5.6%), grade ≥3 neuropathy (1.4 vs 0%), and thrombocytopenia (5.7 vs 0.3%) [54]. This pattern was also noted in the ATEMPT trial, which will be discussed separately, involving patients with small, node-negative, HER2 positive breast cancer [56].

Fam-trastuzumab deruxtecan-nxki (T-Dxd, Enhertu®) is a newer antibody-drug conjugate which links the antibody trastuzumab (T) to the topoisomerase I inhibitor deruxtecan (Dxd), a structural analog to camptothecin [57]. T-Dxd gained FDA approval for use in trastuzumab-resistant metastatic HER2+BC in 2019 following the results of a single-arm phase 2 trial, DESTINY-Breast01, which reported an objective response rate (ORR) of 60.9% and disease control rate (DCR) of 97.3% [57-58]. This was an impressive response, especially given the fact that patients were heavily pretreated with a median of 6 prior lines of therapy. Adverse events included a high rate of all-grade interstitial lung disease (13.6%), with 4 patients experiencing grade 5 toxicity (2.2%). This eventually led to a head-to-head comparison of T-Dxd to T-DM1 via DESTINY-Breast03 to determine the best appropriate second line therapy for metastatic HER2+BC [59]. Interim analysis demonstrated that ORR with T-Dxd remained impressively high at 79.1% versus 34.2% with T-DM1 (p< 0.0001) whereas 1 year OS was reported at 94.1% for T-DXd and 85.9% for T-DM1. Rates of interstitial lung disease were higher at 10.5% versus 1.9% respectively, though all cases involved were either grade 1 or 2 toxicities with only 1 patient experiencing grade 3 toxicity. There were no grade 4 or 5 pneumonitis in this trial. Given the results of both trials, researchers are now investigating whether T-Dxd should replace T-DM1 in the adjuvant setting for high risk patients with residual disease after neoadjuvant therapy (DESTINY-Breast05, NCT04622319) [60]. Whether there will be benefit to using T-Dxd for small node-negative HER2+BC has yet to be investigated.

Newer antibody drug-conjugates are in the development, including ARX788 (anti-HER2 with microtubule inhibitor payload), ZW49 (dual anti-HER2 with auristatin payload), and SYD985 (anti-HER2 antibody with duocarmycin payload). Interim results from the phase 3 TULIP trial (NCT03262935) involving SYD985 (vic-trastuzumab duocarmazine) versus physician’s choice (lapatinib or trastuzumab based chemotherapy regimens) in trastuzumab-refractory metastatic HER2+BC patients were recently released [61]. Researchers found that SYD985 improved both centrally reviewed median PFS (7.0 vs 4.9 months, p=0.002) and OS (HR 0.83, p=0.153), though OS data has yet to mature. Interestingly, ORR was the same between both groups. Additionally, rates of pneumonitis reached 7.6% with two grade 5 events in patients receiving SYD985 and the discontinuation rate due to adverse events was noticeably higher in the SYD985 arm (35.4% vs 10.2%). Nevertheless, initial data appears promising and survival data will be eagerly awaited by clinicians and regulators.

1.5. Small Tyrosine Kinase Inhibitors (TKIs)

Lapatinib was the first oral, small molecule, reversible tyrosine kinase inhibitor (TKI) with dual-HER family activity (HER1 and HER2) to show efficacy in the management of metastatic HER2+BC [62-63]. It received FDA approval in 2007 for trastuzumab-refractory metastatic HER2+BC after it was found to improve time to progression (TTP) from 4.4 months to 8.4 months (p<0.001) and mPFS from 4.1 to 8.4 months (p<0.001) compared to capecitabine monotherapy respectively [64]. Given clinical evidence showing reductions in CNS progression when used in combination with capecitabine, lapatinib became of particular interest in those with metastatic disease involving the central nervous system (CNS) as trastuzumab demonstrated minimal blood brain barrier permeability [65-66].

Neratinib, an irreversible inhibitor of HER1, HER2, and HER4, initially received FDA approval in 2017 for use as adjuvant therapy for non-metastatic HER2+BC following the interim results of the phase 3 ExteNET trial, which randomized patients to either sequential neratinib therapy or placebo following 1 year of adjuvant trastuzumab therapy. Two-year iDFS improved from 91.6% to 94.2% (HR 0.67, p = 0.0091) with the majority of benefit observed in the HR+ population (iDFS 91.7 vs. 95.4 in the placebo and neratinib arms respectively; HR 0.51, p = 0.0013) [67]. However, neratinib treatment resulted in excess GI toxicity (40% experienced grade ≥3 diarrhea). Interestingly, when 5-year follow up data was later analyzed, the cumulative incidence of CNS recurrence at 5 years was 0.7% with neratinib and 2.1% with placebo, further highlighting the potential added benefit of small TKIs [68]. One of the limitations of the ExteNET study is that it began enrollment before either T-DM1 or pertuzumab became standard-of-care therapies for non-metastatic HER2+BC, so it is difficult to interpret the data for adjuvant neratinib in the context of drug approvals that followed. Neratinib also received approval for metastatic HER2+BC when used in combination with capecitabine following the results of the NALA trial. This trial found that mean PFS was improved with use of capecitabine plus with neratinib over capecitabine plus lapatinib (8.8 vs 6.6 months, p=0.0003), though no difference in OS was noted [69]

The newest TKI, tucatinib, received FDA approval following the phase 3 HER2CLIMB study which found more compelling evidence of CNS penetration in patients with metastatic HER2+BC refractory to trastuzumab, pertuzumab, and T-DM1. Among those with CNS involvement, the addition of tucatinib to trastuzumab and capecitabine improved 1 year PFS from 0% to 24.9% (p<0.001) [70].

2.0. Outcomes of patients with small, node-negative HER2+ breast cancer:

Patients with small (T1mic, T1a, T1b), node-negative, HER2+BC represent a unique population. Despite having a pathologic and prognostic stage 1 cancer, these patients have historically been documented as carrying a higher risk of disease recurrence when compared to their HER2-negative counterparts [71]. The most cited example of this is from Gonzalez et al. that retrospectively analyzed recurrence data from untreated patients diagnosed with T1a-bN0 disease and reported an unadjusted 5-year recurrence-free survival (RFS) of 77.1% versus 93.7% in HER2-positive and negative patients respectively (p<0.001) along with a 5-year distant RFS (DRFS) of 86.4% vs 97.2%, respectively (p<0.001). Though small scale (n=98) and often criticized due to a lack of adjuvant endocrine therapy (ET) measures (only 51.7% of the 60 patients with HR+ breast cancer received ET), this study has remained a key justification for the pursuit of treatment in the small, node-negative, HER2+ population.

A separate pre-trastuzumab era retrospective analysis performed by Curigliano et al. that same year (2009) reported a drastically different estimate of recurrence risk for T1a-bN0 patients [72]. For all matched patients with HR-negative disease, they found the 5-year iDFS to be 91% in those who expressed HER2 versus 92% in HER2-negative counterparts (p=0.091). Conversely, in all matched HR+ participants, HER2+ expression (triple-positive breast cancer) was correlated with a 5-year iDFS of 92% versus 99% in HR+HER2-negative patients (p=0.013), suggesting that hormone receptor status plays an important prognostic role when estimating HER2+BC recurrence risk. In this study, 92.4% of eligible HR+ patients received adjuvant endocrine therapy and 46.5% of HR-negative patients received adjuvant chemotherapy.

When looking at prospective data for answers about recurrence risk in patients with small, node negative HER2+BC, the majority of adjuvant and neoadjuvant trials have focused on high risk, node-positive HER2+BC. Those with either T1mic (<0.1cm), T1a (0.1-≤0.5cm), or T1b (>0.5cm-≤1.0cm) node-negative disease were often excluded or only represented a small minority of enrolled patients (as seen in BCIRG-006), which resulted in lack of level 1 evidence to guide treatment for such patients [20]. As a result, many national guideline committees have been unable to firmly recommend anti-HER2 therapies for this patient subset. Below we will review prospective and retrospective studies that attempted to establish evidence for or against adjuvant systemic therapy for patients with small, node-negative, HER2+BC. Table 1 summarizes available data from these studies for ease of comparison.

Table 1:

Comparison of prior retrospective and prospective studies involving small node-negative HER2+ invasive breast cancer

Study	Study type	Dates studied	Median follow up	Total HER2+ T1 N0 patients	Adjuvant chemotherapy with or without trastuzumab	Grade	Node status	ER positivity with HER2	Endocrine therapy for TPBC	Recurrence rate	Survival rate	Adverse events
Cao et al. BCRT83	Retrospective	2004-2017	3.3 years	Trastuzumab T1a: 170 (17.38%) T1b: 285 (29.14%) T1c: 523 (53.48%) Combo T1a: 3222 (15.21%) T1b: 5688 (26.85%) T1c: 12272 (57.94%)	Trastuzumab alone 4.4% Combo 95.6%	Grade 3 Trastuzumab: 445 (45.59%) Combo: 11353 (53.04%)	N0 only	Trastuzumab 783 (77.3%) Combo 16096 (72.28%)	100%	N/A	Propensity matched 3:1 3-year OS: Trastuzumab: 94.1% Combo: 98.1% 5-year OS: Trastuzumab: 90.6% Combo: 97.1% p = 0.041	N/A
He et al. CCR89	Retrospective	1998-2009	10.3 years	Untreated: T1a/mic: 101 (40.6%) T1b: 7 (3.9%) T1c: 27 (17.2%) Chemo T1a/mic: 69 (27.7%) T1b: 34 (18.8%) T1c: 40 (25.5%) Combo T1a/mic: 79 (31.7%) T1b: 140 (77.3%) T1c: 90 (57.3%)	Untreated: 249 Chemo: 181 Combo: 157	Grade 3 Untreated: 67.1% Chemo: 76.2% Combo: 79.0%	N0 only	Untreated: 158 (63.5%) Chemo: 88 (48.6%) Combo: 96 (61.1%)	Untreated: 78.4% Chemo: 89.8% Combo: 91.7%	Unadjusted 10-year iDFS Untreated: 81.0% (75.8-86.5%) Chemo: 65.4% (58.6-73.0%) Combo: 97.3% (94.7-99.9%) 10-year DRFS Untreated: 86.7% (82.2-91.5%) Chemo: 69.7% (63.1-77.0%) Combo: 97.2% (94.6-99.9%) Multivariable analysis 10-year iDFS Untreated: 1.0 (reference) Chemo: 0.884 (0.553-1.412) Combo: 0.071 (0.025-0.204) 10-year DRFS Untreated: 1.0 (reference) Chemo: 1.151 (0.681-1.944) Combo: 0.106 (0.037-0.310)	Unadjusted 10-year BCSS Untreated: 91.1% (86.6-94.5%) Chemo: 72.8% (66.3-80.0%) Combo: 93.7% (89.7-97.8%) 10-year OS Untreated: 79.0% (73.5-84.9%) Chemo: 72.8% (66.3-80.0%) Combo: 93.7% (89.7-97.8%) Multivariable analysis 10-year BCSS Untreated: 1.0 (reference) Chemo: 1.156 Combo: 0.116 10-year OS Untreated: 1.0 (reference) Chemo: 1.0 (reference) Combo: 0.333 (0.182-0.609)	N/A
Parsons et al. JNCCN82	Retrospective	2010-2013	3-6 years	Untreated T1mic: 1073 (19%) T1a: 2245 (39%) T1b: 1199 (21%) T1c: 1203 (21%) Treatment T1mic: 379 (2%) T1a: 1939 (13%) T1b: 4117 (27%) T1c: 8993 (58%)	Untreated T1mic: 1073 (73.9%) T1a: 2245 (53.7%) T1b: 1199 (22.6%) T1c: 1203 (11.8%) Treatment T1mic: 379 (26.1%) T1a: 1939 (46.3%) T1b: 4117 (77.4%) T1c: 8993 (88.2%)	Grade 3 Untreated: 29% Treated: 51%	N0 only	Untreated: 72% Treated: 70%	82%	N/A	Propensity matched 1:1 5-year OS Treated T1mic: 89.1% [81.8-93.5] T1a: 95.4% [93.2-96.9] T1b: 97.1% [95.1-98.4] T1c: 95.9% [93.5-97.5] Untreated T1mic: 99.1% [96.6-99.8] T1a: 96.9% [94.1-98.3] T1b: 92.3% [88.5-94.9] T1c: 91.5% [88.4-93.9]	N/A
Vaz-Luis et al. JCO80	Retrospective	2000-2009	5.5 years	T1a: 216 (41.5%) T1b: 304 (58.5%) T1ab: 520 (100%) TPBC: 334 (64.2%) HER2+: 186 (35.8%)	Untreated T1a: 151 (69.9%) T1b: 106 (34.9%) T1ab: 257 (49.4%) TPBC: 191 (57.2%) HER2+: 66 (35.5%) Combo or chemo alone: TPBC T1a: 33 (24.4%) T1b: 110 (55.2%) T1ab: 143 (42.8%) HR-HE2+ T1a: 32 (39.5%) T1b: 88 (83.8%) T1ab: 120 (64.5%) All HER2+ T1a: 55 (26.7%) T1b: 198 (65.1%) T1ab: 253 (49.6%)	Grade 3: Untreated T1a: 23% Treated T1a: 71% Untreated T1b: 18% Treated T1b: 58%	N0 only	64.2%	85%	Unadjusted 5-year iDFS Untreated TPBC T1a: 86% [76-92%] T1b: 86% [76-92%] Treated TPBC: T1a: 100% T1b: 90% [81-95%] Untreated HR− HER2+: T1a: 84% [69-92%] T1b: 68% [40-86%] Treated HR− HER2+: T1a: 89% [70-96%] T1b: 94% [86-97%] 5-year DRFS Untreated TPBC T1a: 96% [89-98%] T1b: 94% [86-98%] Treated TPBC: T1a: 100% T1b: 96% [88-99%] Untreated HR− HER2+: T1a: 93% [80-98%] T1b: 94% [63-99%] Treated HR− HER2+: T1a: 100% T1b: 94% [85-97%]	Unadjusted 5-year BCSS Untreated TPBC T1a: 99% [90-100%] T1b: 98% [91-99%] Treated TPBC: T1a: 100% T1b: 100% Untreated HR− HER2+: T1a: 95% [81-99%] T1b: 100% Treated HR− HER2+: T1a: 100% T1b: 96% [89-99%] 5-year OS Untreated TPBC T1a: 95% [88-98%] T1b: 95% [88-98%] Treated TPBC: T1a: 100% T1b: 99% [90-100%] Untreated HR− HER2+: T1a: 93% [79-98%] T1b: 100% Treated HR− HER2+: T1a: 100% T1b: 95% [86-98%]	N/A
Fehrenbacher et al. JCO81	Retrospective	2000-2006	5.8 years	T1a: 96 (41.0%) T1b: 118 (50.4%) T1ab: 214 (91.4%)	Untreated T1a/mic: 100 (86.2%) T1b: 71 (60.2%) T1ab: 171 (73.1%) Combo or chemo alone T1a/mic: 15 (13.8%) T1b: 45 (39.8%) T1ab: 60 (26.9%) Combination therapy T1a/mic: 6 (5.2%) T1b: 10 (8.5%) T1ab: 16 (6.8%) Chemo alone T1a/mic: 9 (7.8%) T1b: 35 (29.7%) T1ab: 44 (18.8%)	Grade 3 T1a/mic: 18.1% T1b: 35.6% T1ab: 26.9%	N0 only	T1a/mic: 51.7% T1b: 66.1% T1ab: 59.0%	T1a/mic: 70.8% T1b: 84.6% T1ab: 81.2%	Unadjusted 5-year RFI Untreated T1a/mic: 97.0% [90.0-99.0] T1b: 91.9% [81.5-96.6] T1ab: 94.9% [90.0-97.4] TPBC T1ab: 94.9 [88.0-97.9] HR-HER2+ T1ab: [85.5-98.4] Combination therapy T1a/mic: 100% T1b: 100% T1ab: 100% TPBC T1ab: 100% HR-HER2+ T1ab: 100% Chemo alone T1a/mic: 100% T1b: 87.3% [69.6-95.1] T1ab: 90.2% [75.8-96.2] TPBC T1ab: 94.4 [66.6-99.2] HR-HER2+ T1ab: [65.0-95.7]	N/A	N/A
Rodrigues et al. Annals of Oncology84	Retrospective	2001-2010	3.7 years	Untreated T1a: 51 (41.5%) T1b: 72 (58.5%) Treated T1a: 26 (20.2%) T1b: 103 (79.8%)	Untreated T1a: 51 (100%) T1b: 72 (100%) Treated Combo: 100%	Grade 3 Untreated: 17.9% Treated: 46.9%	N0 only	Untreated 94 (76.4%) Treated 60 (46.5%)	Untreated 81 (86.2%) Treated 59 (98.3%)	Exploratory subgroup analysis 3.3-year iDFS Untreated T1ab: 93% TPBC: 96% HR-HER2+: 84% LVI+: 73% LVI−: 96% Treated T1ab: 99% TPBC: 100% HR-HER2+: 98% LVI+: 100% LVI−: 99%	N/A	N/A
Kiess et al. Cancer88	Retrospective	2002-2008	Non-trastuzumab 7.2 years Trastuzumab: 3.9 years	Non-trastuzumab: T1ab: 17 (24.2%) Trastuzumab: T1ab: 25 (24.5%)	Non-trastuzumab Untreated: 19 (27.1%) Chemo alone: 51 (72.9%) Trastuzumab: Combo: 155 (100%)	N/A	N0 only	Non-trastuzumab: 67% Trastuzumab 63%	Non-trastuzumab: 95.7% Trastuzumab: 93.8%	Adjusted for follow up 3-year LRFS Non-trastuzumab: 90% [83-97%] Trastuzumab: 99% [97-100%]	N/A	N/A
McArthur et al. Cancer87	Retrospective	2002-2004	Non-trastuzumab 6.5 years Trastuzumab: 3.0 years	Non-trastuzumab: T1a: 23 (22%) T1b: 22 (21%) Trastuzumab: T1a: 12 (8%) T1b: 42 (27%)	Non-trastuzumab Untreated: 36 (34.0%) Chemo alone: 70 (66.0%) Trastuzumab: Combo: 155 (100%)	Grade 2-3 Non-trastuzumab: 91% Trastuzumab: 97%	Non-trastuzumab N0: 97% N0 (i+): 3% Trastuzumab N0: 97% N0 (i+): 3%	Non-trastuzumab: 60% Trastuzumab 63%	Non-trastuzumab: 98.4% Trastuzumab: 96.9%	Unadjusted 3-year iDFS All tumor sizes Non-trastuzumab: 82% [74-90%] Trastuzumab: 97% [94-100%] Tumor size ≤1cm: Non-trastuzumab: 78% [66-91%] Trastuzumab: 95% [87-100%] 3-year LRFS All tumor sizes Non-trastuzumab: 92% [86-97%] Trastuzumab: 98% [95-100%] Tumor size ≤1cm Non-trastuzumab: 92% [84-100%] Trastuzumab: 96% [90-100%] 3-year DRFS All tumor sizes Non-trastuzumab: 95% [90-99%] Trastuzumab: 100% Tumor size ≤1cm Non-trastuzumab: 97% [92-100%] Trastuzumab: 100%	Unadjusted 3-year OS All tumor sizes Non-trastuzumab: 97% [93-100%] Trastuzumab: 99% [98-100%] Tumor size ≤1cm Non-trastuzumab: 98% [93-100%] Trastuzumab: 98% [95-100%]	N/A
Curigliano et al. JCO72	Retrospective	1999-2006	4.6 years	T1a/mic TPBC: 34 (43.0%) HER2+: 51 (71.8%) T1b TPBC: 45 (57.0%) HER2+: 20 (28.2%)	Untreated TPBC: 8 (10.1%) HER2+: 38 (53.5%) Chemo alone TPBC: 20 (25.4%) HER2+: 31 (43.7%)	Grade 3 TPBC: 35.4% HER2+: 60.6%	N0 only	52.7%	HT alone: 64.6% HT+Chemo: 24.1%	Unadjusted 5-year iDFS TPBC T1a/mic: 88% HER2+ T1a/mic: 93% TPBC T1b: 95% HER2+ T1b: 85 TPBC w/ET: 96% TPBC w/o ET: 57%	N/A	N/A
Gonzalez-Angulo et al. JCO71	Retrospective	1990-2002	6.2 years	T1a: 43 (43.9%) T1b: 55 (56.1%)	Untreated 98 (100%)	Grade 3 73.1%	N0 only	61.2%	51.7%	Unadjusted 5-year DRFS 86.4% [77.3-92.1%] 5-year RFS 77.1% [67-84.5%]	N/A	N/A
Tolaney et al. JCO56 (ATE MPT trial)	Prospective	2013-2016	3.9 years	T-DM1 T1a: 57 (15%) T1b: 127 (33%) TH T1a: 13 (11%) T1b: 40 (35%)	Combo 22.9% HER2 only 77.1%	Grade 3: T-DM1: 57% TH: 54%	T-DM1: N0: 95% N1mic: 5% TH: N0: 99% N1mic: 1%	T-DM1: 75% TH: 74%	Unknown	3-year RFI T-DM1: 99.2% [98.2-100%] TH: 94.3% [89.9-98.8%] 3-year iDFS T-DM1: 97.8% [96.3-99.3%] TH: 93.4% [88.7-98.2%] 3-year iDFS (T-DM1 alone) TPBC: 97.5% [95.7-99.4%] HR-HER2+: 98.7% [96.2-100%] Tumor <1 cm: 98.7% [96.9-100%] Tumor ≥1 cm: 97.2% [95.0-99.4%]	N/A	Symptomatic CHF T-DM1: 0.8% TH: 1.8% Asymptomatic EF decline: T-DM1: 0.5% TH: 3.5% Grade >=2 Neuropathy: TDM1: 11.2% TH: 22.8% Early termination: TDM1: 23.5% TH: 14.9%
Tolaney et al. NEJM75, BCRT76 (APT trial)	Prospective	2007-2010	6.5 years	T1a: 68 (16.7%) T1b: 124 (30.5%)	Combo 100%	Grade 3: 56.2%	N0: 98.5% N1mic: 1.5%	64.0%	Unknown	3-year iDFS 98.7% [97.6-99.8%] 3-year LRFI 99.2% [98.4-100%] 7-year iDFS 93.3% [90.4%-96.2%] 7-year LRFI 98.6% [97.4-99.8%]	N/A	Symptomatic CHF: 0.5% Asymptomatic EF decline: 3.2% Grade >=2 neuropathy: 13.1% Early termination: 12.3%
Jones et al. Lancet Oncol74 (US Oncology Research)	Prospective	2007-2009	3.0 years	T1a/mic: 17 (3.4%) T1b: 90 (18.3%) T1c: 224 (45.2%) T2: 162 (32.9%)	Combo 100%	N/A	N0: 391 (79.3%)	64.9%	Unknown	2-year iDFS All: 97.8% (96.0-98.8%) T1a-b N0: 100% 3-year iDFS All: 96.9% (94.8%-98.1%) T1a-b N0: 100%	2-year OS All: 99.2% (97.8-99.7%) T1a-b N0: 100% 3-year OS All: 98.7% (97.1%-99.4%) T1a-b N0: 100%	Symptomatic CHF: 0.2% Asymptomatic EF reduction: 5.1% Grade ≥2 neuropathy: 2.2% Early termination: 9.2%
Slamon et al NEJM73 (BCIRG-006 trial)	Prospective	2001-2004	5.4 years	AC-T T1: 439 (41%) AC-TH T1: 413 (38%) TCH T1: 431 (40%)	Chemo alone 33.3% Combo 66.7%	N/A	AC-T N0: 29% AC-TH N0: 28% TCH N0: 28%	AC-T: 54% AC-TH: 54% TCH: 54%	Unknown	5-year iDFS All patients AC-T 75% AC-TH: 84% TCH: 81% N0 subgroup AC-T: 85% AC-TH: 93% TCH: 90% Size <1cm subgroup AC-T: 72% AC-TH: 86% TCH: 86%	5-year OS All patients AC-T: 87% AC-TH: 92% TCH: 91%	Symptomatic CHF: AC-T: 0.7% AC-TH: 2.0% TCH: 0.4% Asymptomatic EF reduction: AC-T: 11.2% AC-TH: 18.6% TCH: 9.4% Any grade neuropathy: AC-T: 53.8% AC-TH: 56.0% TCH: 40.3% Early termination: AC-T: 11.2% AC-TH: 18.6% TCH: 9.4%

Abbreviation: AC-TH: adriamycin, cyclophosphamide, taxol, trastuzumab; CHF: congestive heart failure; EF: ejection fraction; BCSS: breast cancer-specific survival; DDFS: distant disease-free survival; DDRS: distant disease recurrence survival; iDFS: invasive disease-free survival; LFRI: local recurrence-free interval; LRFS: local recurrence-free survival; OS: overall survival, RFI: recurrence-free interval; TPBC: Triple-positive breast cancer

2.1. Prospective data:

2.1.1. BCIRG-006

The earliest HER2-directed study to include this unique population was BCIRG-006, which was a phase 3 trial that randomly assigned 3222 women with HER2+ early-stage breast cancer to receive either AC-T (doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks), AC-TH (AC-T followed by 1 year of trastuzumab), or TCH (docetaxel and carboplatin and 1 year of trastuzumab) [20, 73]. Of the 3222 women included, 29% were node-negative and 40% had T1 disease, making this the first major trastuzumab trial to allow those with a tumor size ≤1cm to enroll. The primary end point of 5-year iDFS was 75%, 84%, and 81% for AC-T, AC-TH (p<0.001, all p-values as compared to AC-T arm), and TCH (p=0.04) respectively. Anecdotally, it is worth noting that of the 58 node-negative patients enrolled with tumors <1cm who went on to receive chemotherapy alone (AC->T), the 5-year iDFS was 72%, whereas those who received either TCH (n=44) or AC-TH (n=46) both had a 5-year iDFS of 86%. Conversely, for those with tumors ≥1 to <2cm, the 5-year iDFS was 86% (n=303), 87% (n=283), and 86% (n=300) respectively, illustrating that the majority of benefit seen in iDFS was likely derived in those with tumors ≥2cm. However, both subgroup analyses involved small numbers, making any formal comparison of statistical significance problematic. Regarding node negativity, a statistically significant benefit was seen with AC-TH (iDFS 93% vs 85%, p=.0028), but not TCH (90% vs 85%, p=.057).

2.1.2. US Oncology Research study

A single arm phase 2 study by the US Oncology Research team set out to see if 4 cycles of docetaxel, cyclophosphamide, and trastuzumab would be of benefit in HER2+BC patients with T1 & T2 disease. Additionally, they performed an exploratory analysis to determine if either TOP2A or c-Myc amplification play a role in treatment resistance [74]. Out of the 439 patients they enrolled, 90 were T1a-b N0. They were able to demonstrate that 3-year iDFS and OS in the T1a-b N0 patients was 100% among the 90 participants. Out of all 439 participants, 1 (0.2%) developed symptomatic CHF and 25 (5.1%) had an asymptomatic EF decline below 50%. Overall, TOP2A and c-Myc amplification status had no impact on reported clinical outcomes. Drawbacks of the study include its short follow up period and its single arm design which ultimately made it difficult to assert docetaxel, cyclophosphamide, and trastuzumab as a standard treatment regimen.

2.1.3. APT trial

The first major prospective study designed specifically to assess the response of small, node-negative HER2+BC to de-escalated adjuvant combination therapy was the APT (Adjuvant Paclitaxel & Trastuzumab) trial [75-76]. The study enrolled 406 node-negative patients with tumors ≤3cm who received treatment with 12 courses of weekly paclitaxel and 1 year of trastuzumab (TH) in a single-arm fashion with the primary outcome being iDFS. With a median follow up of 6.5 years, patients were found to have a 3- & 7-year iDFS of 98.7% and 93.3%, respectively.

The major criticism surrounding this study was its single-arm nature, however a substantial sample size would have been necessary in order to highlight such a small magnitude of benefit if a control arm had been used. One might argue that the high iDFS reported would suggest that any harm gained through overtreatment is likely minimal, but this would not take into account significant adverse effects that develop from this treatment, both long-term and short-term. In this study alone, 12.3% of participants withdrew from the intervention primarily due to drug toxicities. Neuropathy was a common adverse event, with 13.1% of patients developing ≥ grade 2 neuropathy. Asymptomatic LVEF decline was seen in only 3.2% of participants whereas 0.5% developed symptomatic CHF.

Additionally, though T1 tumors were included in this study, the majority of participants were T1c (42%) so perhaps this T1c cohort derived the majority of the benefit. T1mic patients were also included, though only a small proportion were enrolled (2.2%). Similarly, the study enrolled only 68 patients (16.7%) with T1a disease. Finally, though our review is focused on T1N0 management, questions have also arisen regarding whether this de-escalated regimen should be extended to T2N0 patients with tumor size between 2 and 3 cm. However, only 8.9% of study population had tumors that were 2-3 cm in diameter making it difficult to know whether TH regimen could replace standard adjuvant regimens for this patient population. One thing is for certain; the iDFS rates appear to be reproducible in both the real-word setting and in subsequent trials, which is promising [56, 77-78].

2.1.4. ATEMPT trial

The ATEMPT trial took this data a step further by narrowing its focus to T1N0 HER2+BC as it explored the use of T-DM1 in this population [56]. Patients were randomized in a 3:1 fashion to receive adjuvant therapy with either T-DM1 or TH. The co-primary endpoints were 3-year iDFS in the T-DM1 arm and comparison of clinically relevant toxicities between the two arms. Of note, the study was not powered to compare efficacy between the two study arms. After 3 years of median follow up, the iDFS was 97.8% with T-DM1 versus 93.4% with TH. When stratified by tumor size, those with tumors <1cm had a 3-year iDFS of 98.7% (95%CI 96.9-100%) vs 97.2% (95%CI 95.0-99.4) for those ≥1cm. Additionally, when stratified by HR status, those found to be HR+ had a 3-year iDFS of 97.5% (95%CI 95.7-99.4%) compared to 98.7% (95%CI 96.2-100%) for the HR− cohort.

The authors promoted T-DM1 as a more tolerable treatment regimen in the publication. However, 17.5% of T-DM1 patients had to stop treatment early due to unacceptable toxicities (versus only 6% in the TH group) and only 76.5% of patients were able to complete T-DM1 therapy (versus 85.1% in the TH group). Additionally, though T-DM1 was observed to result in lower rates of peripheral neuropathy (11 vs 23%, p=0.0031), the 3 most common reasons for T-DM1 discontinuation were liver enzyme elevations (28%), neuropathy (19%) and thrombocytopenia (19%). Cardiotoxicity rates were low for both treatment arms in terms of asymptomatic decline in LVEF (0.5% T-DM1 vs 3.5% TH) and symptomatic CHF (0.8% T-DM1 vs 1.8% TH). In order to address concerns regarding T-DM1 toxicity, a follow-up study (ATEMPT 2.0, NCT04893109) has entered its active accrual phase and will be randomizing T1N0 HER2+BC patients to receive either standard TH therapy or T-DM1 for 6 cycles (versus the 17 cycles in the original ATEMPT study) followed by trastuzumab for 11 cycles [79].

2.2. Retrospective data:

2.2.1. Recurrence risk

To better evaluate the benefit of treatment specific to small node-negative breast cancer, Vaz-Luis et al constructed a prospective cohort study using the National Comprehensive Cancer Network (NCCN) database [80]. The study reviewed recurrence and survival data from 2000-2009 from 4113 patients with T1aN0 and T1bN0 disease, regardless of receptor status, who either went untreated or received a combination of adjuvant chemotherapy with or without trastuzumab. In the unadjusted HR+ HER2+ subgroup, those with untreated T1aN0 tumors carried a 5-year iDFS of 86% (n=102 [CI 76-92%]) vs 100% (n=33 [CI 100%]) in the treatment arm. For T1bN0 TPBC, the gap narrowed; 5-year iDFS was 86% (n=89 [CI 76-92%]) vs 90% (n=110, [CI 81-95%]) in the untreated and treated arms respectively. In the HR− HER2+ subgroup, the T1aN0 patients were found to have a 5-year iDFS of 84% (n=49 [CI 69-92%]) versus 89% (n=32 [CI 70-96%]). Alternatively, for patients in the HR− HER2+ T1bN0 subgroup, iDFS dropped to 68% (n=17 [CI 40-86%]) versus 94% (n=88 [CI 86-97%]) though the sample size was quite small. Despite the findings above and a median follow up of 5.5 years, no meaningful difference in DRFS, breast cancer-specific survival (BCSS), or OS was observed, with the HR− HER2+ BC subgroup sustaining a 5-year OS of 100% (vs 100% untreated) and 95% (vs 93% untreated) for T1a and T1b patients respectively.

When looking at other outcome data that utilizes endpoints outside of DFS, the benefit of adjuvant chemotherapy and trastuzumab appears less prominent [81]. Fehrenbacher et al published a retrospective analysis involving 171 untreated HER2+ T1a-b N0 patients and compared their 5-year recurrence-free interval (RFI) to those who received chemotherapy alone (n=44) or combination therapy (n=16). With a median follow up of 5.8 years for patients studied from 2000-2006, the unadjusted 5-year RFI for untreated T1a-bN0 disease was 94.9% [CI 90.0-97.4%] compared to 90.2% [CI 75.8-96.2%] with chemotherapy alone and 100% with combination of trastuzumab and chemotherapy. However, given the low patient numbers, this conclusion is exploratory at best, and due to its unadjusted nature, it does not account for the propensity of providers to treat younger healthier patients with chemotherapy compared to geriatric or unfit patients.

2.2.2. Propensity-matched retrospective data

Selection bias has plagued prior unadjusted retrospective analyses given that fit, young patients or those with disease perceived to carry higher risk features are chosen for adjuvant therapy whereas deconditioned, older patients or those perceived to have low risk features end up untreated, resulting in an unbalanced comparison. Being able to propensity match patients based on clinicopathologic features can help reduce this issue, but this requires large scale datasets to accurately perform.

As individualized patient medical data has become increasingly archived electronically throughout the decades, large scale national cancer databases have started to arise, becoming a viable option for large, multi-institutional retrospective analyses. In the realm of small, node-negative, HER2 positive breast cancer, this was best illustrated by Parsons et al. with their National Cancer Database (NCDB) study involving 5720 untreated T1N0 patients who were propensity matched 1:1 to 15428 controls who had received adjuvant HER2-containing chemotherapy regimens [82]. Matching was performed to adjust for confounding patient, tumor, and facility factors that could impact the receipt of chemotherapy or patient outcomes (although details about specific factors used are not clear in the publication). With a primary end point of 5-year OS, they found a worsening association between OS and adjuvant chemotherapy use in those with T1mic disease (89.1% [n=379] vs 99.1% [n=1073] in treated vs untreated groups respectively, p=0.0006). Regarding T1a patients, no clear improvement was seen (95.4% [n=1939] vs 96.9% [n=2245] respectively, p=0.059). Finally, for T1b disease, treated patients carried a higher 5-year OS compared to the untreated group (97.1% [n=4417] vs 92.3% [n=1199], p=0.0016). This same trend was observed in those with T1c disease (95.9% [n=8993] vs 91.5% [n=1203], p=0.0002). Given the size of this study, it became the strongest retrospective evidence supporting the use of adjuvant chemotherapy in T1b and T1c patients. Conversely, considering the lowered OS in T1mic cohorts, this provided a stark warning against use of aggressive chemotherapy practices without supporting evidence. One flaw of the study is that due to outdated terminology used by the NCDB, the authors could not definitively confirm whether treated patients had truly received trastuzumab in addition to chemotherapy. Presumably, the vast majority would have received both trastuzumab and chemotherapy considering the time period included in the study (2010-2013).

This research was followed by another large retrospective analysis through the NCDB by Cao et al. which set out to answer whether the addition of chemotherapy to trastuzumab monotherapy would provide any additional benefit in this T1N0 subset [83]. Within a study period of 2004-2017, they found 22,268 patients treated with combination therapy and 1013 treated with trastuzumab alone, then propensity matched them 3:1 with a primary end point of 5-year OS. Within the propensity-matched analysis, they found that 5-year OS improved to 94.1% with combination therapy versus 90.6% with trastuzumab alone (p=0.041). However, on multivariable Cox proportional hazard regression, this benefit from combination therapy became insignificant (HR 0.655, 95%CI 0.416-1.033, p = 0.068). It is also unclear if authors ran into similar difficulties distinguishing retrospective trastuzumab administration data through the NCDB as described by Parsons et al. given the overlapping study periods.

2.2.3. Small tumors with high-risk features

Regardless of what the universally accepted recurrence risk for the general T1N0 HER2+ population might be, prescribers often argue that the presence of high-risk features such as lymphovascular invasion (LVI) or high grade disease (which are common in HER2+ tumors) should justify the administration of HER2-directed combination therapy. In the aforementioned retrospective analyses, unadjusted treatment arms often involve significantly higher rates of LVI and grade 3 disease, yet with treatment these high-risk patients are consistently able to fare equally to their untreated, lower risk counterparts. A retrospective analysis by Rodrigues et al. observed that the 3.3-year iDFS for untreated patients with HER2+ T1a-b disease found to be LVI+ (n=12) was 73% vs 100% for those on combination therapy (n=26) [84]. For the LVI− subgroups (n=105 and 99 respectively), 3.3-year iDFS was 96% versus 99% with combination therapy. Given the small sample sizes, no formal statistical analysis was conducted regarding LVI status.

Interestingly, within the same multivariable analysis by Cao et al mentioned earlier, data did not support the addition of chemotherapy to trastuzumab in patients with high risk features, including LVI (HR 1.089, 95%CI 0.498-2.381, p = 0.830), grade 3 disease (HR 1.039, 95%CI 0.395-2.736, p = 0.938), age (HR 1.031, 95%CI 0.999-1.064, p = 0.060), and T1c disease (HR 0.849, 95%CI 0.451-1.597, p= 0.611) [83]. However, HR+ status seemed to dictate derived benefit (HR 0.535, 95%CI 0.308-0.930, p = 0.027) along with private insurance status (HR 0.464, p=0.036), whereas African American ethnicity (HR 1.995, p=0.024) and a high comorbidity index (HR 4.320, p = <0.001) were associated with poorer outcomes.

Multifocal disease is another high-risk feature that often leads to the treatment of T1N0 HER2+BC. Si et al. retrospectively compared iDFS between patients with unifocal (n=233) and multifocal (n=126) T1mic breast cancer who had previously undergone concurrent sentinel lymph node biopsies and breast surgery [85]. They found that multifocal disease was linked to the presence of HER2 positivity (p=0.027), positive LVI (p=0.034), higher tumor grades (p=0.001), higher Ki-67 levels (p=0.004), and larger tumor sizes on final pathology (p<0.001), although the axillary metastasis rate was not statistically different between unifocal and multifocal patients (p = 0.0559). They reported that the unadjusted iDFS for multifocal patients was 93.01% vs 98.29% (p = 0.032) compared to unifocal T1mic cN0 breast cancer, regardless of receptor status. However, on multivariate analysis, the only independent predictor of worsened iDFS was nodal status. In the context of the small sample sizes, these results mainly serve a hypothesis-generating role that require further validation.

3.0. Conclusion:

This review serves as an updated summary of available data regarding the use of adjuvant anti-HER2 therapy regimens for T1N0 HER2+BC in the post-trastuzumab era. We also attempted to briefly review and underscore the recent growth in the number of approved HER2-targeting treatment options, which will continue to increase in the future.

When retrospectively reviewing the recurrence risk for untreated T1aN0 and T1bN0 HER2+BC, studies have suggested that HER2 positivity can lead to higher relapse rates compared to HER2-negative counterparts [71, 72]. However, the absolute difference across studies is modest, partially due to the excellent prognosis of T1N0 disease [72]. Estimates of 5-year DFS have ranged anywhere from 68% to 96% [71, 73, 80-89]. This wide range in recurrence risk is due partially to inconsistencies involving the definition of adjuvant clinical outcomes, such as DFS. Decisions involving the censoring of contralateral breast cancers, new non-breast malignancies, and all-cause mortality have been the biggest areas of debate. In addition, small sample sizes within each comparator arm have made it hard to conclude if any distinction truly exists. Finally, given the absence of a standardized recurrence outcome, clinicians are left comparing incompatible metrics across conflicting studies, with the list including DFS, iDFS, DFS ductal carcinoma in situ (DFS-DCIS), RFS, DRFS, local RFS (LRFS), RFI, invasive RFI (IRFI), local RFI (LRFI), and breast cancer free interval (BCFI) to name a few. The definition for each term mentioned above is summarized further in Table 2 based on multiple adopted guidelines, though areas of disagreement still remain [90-94].

Table 2:

Summary of end point definitions based on multiple breast cancer-related guidelines

Event type	Overall Survival (OS)	Breast Cancer Specific Survival (BCSS)	Event free Survival (EFS)	Disease Free Survival (DFS)	Invasive DFS (iDFS)	Invasive Breast Cancer Free Survival (iBCFS)	Relapse or Recurrence Free Survival (RFS)	Distant DFS (DDFS)	Ductal Carcinoma in Situ DFS (DFS-DCIS)	Distant RFS (DRFS)	Local RFS (LRFS)	Recurrence Free Interval (RFI)*	Distant RFI (DRFI)	Local RFI (LRFI)	Breast Cancer Free Interval (BCFI)
Death of any cause	✓	x	✓	✓	✓	✓	✓	✓	✓	✓	✓	x	x	x	x
Death due to any cancer	✓	x	✓	✓	✓	✓	✓	✓	✓	✓	✓	x	x	x	x
Death due to breast cancer	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓
Distant recurrence	x	x	✓	✓	✓	✓	✓	✓	✓	✓	x	✓	✓	x	✓
Regional recurrence	x	x	✓	✓	✓	✓	✓	x	✓	x	✓	✓	x	✓	✓
Ipsilateral invasive recurrence	x	x	✓	✓	✓	✓	✓	x	✓	x	✓	✓	x	✓	✓
New contralateral invasive breast cancer	x	x	✓	✓	✓	✓	x	x	✓	x	x	x	x	x	✓
New contralateral DCIS	x	x	x	?	x	x	x	x	✓	x	x	x	x	x	✓
New ipsilateral DCIS	x	x	x	?	x	x	?	x	✓	x	✓	✓	x	✓	✓
New non-breast invasive cancer	x	x	x	?	✓	x	x	?	✓	x	x	x	x	x	x
Progression of curable cancer prior to surgery	x	x	✓	x	x	x	x	x	x	x	x	x	x	x	x
Death due to cancer treatment	✓	?	✓	✓	✓	✓	✓	✓	✓	✓	✓	x	x	x	x
Lost to follow up	x	x	x	x	x	x	x	x	x	x	x	x	x	x	χ

✓ = event is eligible, x = event is ineligible and/or censored, ? = no consensus

^*RFI has been interchangeably referred to as "Time to Recurrence" (TTR) in clinical studies

The lack of an accepted baseline recurrence risk for this untreated cohort has in turn made it difficult to interpret prospective single-arm studies such as the APT or ATEMPT trials which rely on historical controls [56, 75-76]. Both studies demonstrated an exceptional 3-year iDFS rate of 98.7% and 97.8% respectively, but also come with high percentages of early termination due to unacceptable toxicities (17% T-DM1 versus 6% PT). Whether they be cardiovascular, neurological, hematological, psychological, or financial, these treatments can have multiple unintended consequences. It is unlikely that future prospective trials will offer observation alone to T1N0 patients, nor could any randomized prospective trial support a large enough number of patients needed to measure recurrence risk given the low event rate. The answer will likely need to come from meta-analyses as retrospective studies continue to further catalog periodic data as they mature. In the end, for treatment to be deemed beneficial for these patients, we should expect to see that the degree of added benefit outweighs the risk of harm.

The most recent NCDB study examining trastuzumab monotherapy versus combination therapy demonstrated a significant improvement in OS when patients were propensity matched, but not on multivariable hazard regression. Whether this means anti-HER2 therapy alone is providing the majority of benefit in this patient population has yet to be confirmed and will require further investigation. As seen with the ATEMPT trial, anti-HER2 antibody-drug conjugate monotherapy has become a viable option that does not employ conventional systemic chemotherapy and hence might improve the risk/benefit ratio. ATEMPT 2.0 will help answer the question of whether shorter T-DM1 duration can result in similar improvements to cancer-specific survival, all while limiting toxicities. This may continue to be the trend as newer agents with similar efficacy and improved tolerance reach development, including small molecule TKIs, newer antibody-drug conjugates, and investigational therapies such as bispecific T-cell engagers (BiTEs), cancer vaccines, and others. For now, clinical judgment remains the main determinant until further data becomes available.

Future research will also be focused on identifying more accurate tools that rely on factors other than just tumor size to risk stratify this unique patient population. Similar to HR+ HER2− breast cancer patients, this may require the use of tumor genomics, development of predictive molecular assays, and identification of other intrinsic factors that can aide in better optimization of care.

4.0. Expert opinion:

Evidence supporting the use of anti-HER2-containing adjuvant systemic therapy regimens for patients with small node-negative HER2+BC continues to grow. This is most apparent in those with T1b and T1c disease as illustrated by the largest retrospective analysis to date through the NCDB. While clear gains were noted in T1b and T1c disease, a measurable decline in OS was noted in the T1mic cohorts, both in the matched and unmatched analyses. This is the first time large-scale evidence of harm has been documented with the over-treatment of small HER2+BC., However, this result should be interpreted with some caution given all the drawbacks of retrospective analysis. Prospective studies have confirmed favorable outcomes and relatively low risks associated with adjuvant paclitaxel with trastuzumab or T-DM1 in patients with small, node-negative tumors. This provides the strongest evidence supporting the use of adjuvant systemic chemotherapy in this patient population, particularly in those with T1b and T1c disease. We feel that the biggest limitation of these studies is the use of historical controls for efficacy comparisons, which could skew the results in favor of treatment. Additionally, due to the lack of head-to-head comparisons between chemotherapy agents in this population, it is also unclear whether substituting different NCCN-approved combination regimens would lead to comparable results, including trastuzumab, docetaxel, & carboplatin (TCH), doxorubicin & TCH (ACTH), trastuzumab, docetaxel, & cyclophosphamide (US Oncology Research regimen), or trastuzumab, pertuzumab, and paclitaxel (THP) [14]. Finally, different taxane therapies could be explored in combination with anti-HER2 therapy, including docetaxel (as seen in BCIRG-006 and FinHer), paclitaxel and even nab-paclitaxel.

There have only been a handful of prospective randomized studies that have examined how HER2-directed therapies impact recurrence risk for this unique patient population. The majority of these studies involved not only small node-negative patients, but also those with large tumor sizes, mixed node status, and high risk features. As a result, we often see an overall improvement in recurrence risk within the primary data, but these studies enrolled relatively small numbers of low-risk patients making the interpretation of the results difficult. Prospective studies such as APT and ATEMPT trials examined benefit from chemotherapy specifically in patients with small, node-negative HER2+BC specifically but they again depend on the use of historical controls which is not ideal. Though the majority of retrospective studies mentioned above are limited by sample size and biases inherent to retrospective analyses, they further add to the piling evidence surrounding the growing use of adjuvant chemotherapy in T1N0 HER2+BC.

Though no clear benefit is derived from adjuvant therapy in T1mic and T1a HER2+BC based on large retrospective studies, it is likely that a select group may still benefit from treatment and a need exists for further risk stratification based on combination of intrinsic factors, such as tumor grade, HR status, LVI, tumor-infiltrating lymphocytes (TILs), TOP2A aberrations, CEP17 duplications, PIK3CA mutations, etc [95-97]. Whether anti-HER2 monotherapy alone will suffice remains an area of debate. Conversely, low risk T1b and T1c patients, particularly those with HR+ disease, may be able to be risk-stratified to endocrine therapy alone versus anti-HER2 regimens using genomic data, as seen in the phase 3 MINDACT trial using 70-gene signature MammaPrint® technology [98],

Finally, future studies will need to examine the appropriate duration of adjuvant therapy, particularly for those who would otherwise be poor candidates for standardized treatment, such as patients with underlying cardiac comorbidities, neuropathy, or poor functional status. While prior studies heavily focused on multi-agent anthracycline-based regimens, de-escalated regimens resulted in lowering the risk/benefit ratio. As newer data from ongoing trials such as ATEMPT 2.0 (NCT04893109) and REaCT-HER TIME (NCT04928261) becomes available, we will have a clearer picture regarding optimal anti-HER2 duration and therapy, further improving de-escalation efforts for vulnerable patients with low risk disease, including those with T1N0 HER2+BC.[99].

To summarize, we believe currently available clinical data suggests that trastuzumab therapy in conjunction with conventional chemotherapy can be a viable option in select T1 patients, specifically T1c and T1b disease, though caution should be taken as intrinsic features and competing co-morbidities must also be taken into account. Clinical benefit in T1a and T1mic patients has yet to be demonstrated and evidence suggests that overtreatment is a possibility if a blanket approach is used without consideration of risks and benefits. Whether anti-HER2 duration can be adjusted or anti-HER2 monotherapy should be applied to this cohort remains an active are of investigation.

Article highlights:

• In T1mic and T1a N0 disease, adjuvant HER2-directed chemotherapy remains controversial and studies point towards potential overtreatment.

• In T1b and T1c N0 disease, current retrospective data suggests added treatment benefit based on improved cancer specific survival outcomes and recurrence rates

• Prospective trials have shown impressive rates of iDFS, but no improvements in OS have been demonstrated to date. Furthermore, prospective trials have used historical controls in place of untreated control arms due to the high patient volume required for enrollment in order to evaluate the presence of any statistically significant benefit.