Predictive markers of treatment response to neoadjuvant systemic therapy with dual HER2-blockade

doi:10.21203/rs.3.rs-3801073/v1

Download PDF

Research Article

Predictive markers of treatment response to neoadjuvant systemic therapy with dual HER2-blockade

https://doi.org/10.21203/rs.3.rs-3801073/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated with dual HER2-blockade.

Methods

In this retrospective study, 348 patients with HER2-positive breast cancer were included, who received NAST with docetaxel and carboplatin, combined with trastuzumab and pertuzumab (TCHP). We assessed the effects of HER2 protein expression (3 + vs. 2 + on immunohistochemistry [IHC]) and tumor-infiltrating lymphocyte (TIL) levels (< 30%, low; ≥ 30%, or high) on pCR (ypT0/is and ypN0).

Results

Of the 348 patients with HER2 protein expression data, 278 (79.9%) had HER2 IHC 3+. Among the 305 patients with available TIL data, 121 (39.7%) had high TIL levels. A higher pCR rate was observed in patients with HER2 IHC grade 3+ (71.6% vs. 34.3%, p < 0.001) and high TILs levels (71.9% vs. 57.6%, p = 0.011). After adjusting other clinicopathologic factors, the HER2 IHC 3+ (Odds ratio [OR], 3.66; 95% confidence interval [CI], 1.92–6.96; p < 0.001), high TIL (OR, 1.94; 95% CI, 1.09–3.45; p = 0.024), and hormone-receptor (HR)-negative (OR, 3.33; 95% CI, 1.88–5.91; p < 0.001) were found to be independently associated with pCR. In HR-positive cases, HER2 IHC 3 + and high TILs levels remained independent predictors of pCR but not in HR-negative breast cancer.

Conclusions

Our results suggest that high HER2 protein expression and TIL predict treatment response to neoadjuvant TCHP, especially in HR-positive breast cancer.

Breast neoplasm

Neoadjuvant therapy

HER2-targeted therapy

HER2 expression

Tumor-infiltrating lymphocyte

Over the past decade, the treatment paradigm in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has markedly shifted. Although HER2-positive breast cancer is a biologically aggressive tumor, the revolution in HER2-targeted therapies has significantly improved the prognosis of patients with HER2-positive breast cancer [1, 2]. In addition, the application of neoadjuvant systemic therapy (NAST) in the early stages of HER2-positive breast cancer has increased because NAST has the benefit of reducing the surgical extent and tailoring adjuvant treatment according to its response [3, 4]. As a pathologic complete response (pCR) after NAST predicts a favorable prognosis [5, 6], numerous clinical trials have explored new HER2-targeted therapies to increase the pCR rate in neoadjuvant settings. Among the combinations of neoadjuvant chemotherapy and HER2-targeted therapies, the administration of a dual HER2-blockade with trastuzumab and pertuzumab to anthracycline- or platinum-based chemotherapy showed the highest pCR rate of 50–70% [7–11].

Owing to its excellent response and acceptable toxicity profile, neoadjuvant chemotherapy with trastuzumab and pertuzumab is currently the preferred regimen for patients with HER2-positive breast cancer who are candidates for NAST. Although efforts have been made to identify biomarkers to predict the treatment response to neoadjuvant chemotherapy with trastuzumab and pertuzumab, it remains unclear. Trastuzumab and pertuzumab are monoclonal antibodies that bind to the extracellular subdomain of the HER2 receptor on the cancer cell surface [12]. Moreover, trastuzumab and pertuzumab cause antibody-dependent cell-mediated cytotoxicity effects [12], indicating that immune activation in the tumor microenvironment may affect therapeutic efficacy. Based on the mechanism of action of these HER2-targeted therapies, we hypothesized that HER2 protein expression and stromal tumor-infiltrating lymphocyte (TIL) levels evaluated by immunohistochemistry (IHC) may predict the treatment response in HER2-positive breast cancer.

This study aimed to identify the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer who underwent NAST with platinum-based chemotherapy plus trastuzumab and pertuzumab. In particular, we compared pCR rates according to HER2 protein expression (IHC 2 + vs. IHC 3+) and TIL levels, stratified by hormone receptor (HR) status.

Study population

The study protocol was reviewed and approved by the Institutional Review Board of Gangnam Severance Hospital, Yonsei University, Seoul, Korea (IRB no. 3-2023-0017). This study adhered to the principles of the Declaration of Helsinki. The requirement for written informed consent was waived because of the retrospective study design.

Between April 2015 and December 2022, we retrospectively identified 355 women with HER2-positive breast cancer who received neoadjuvant systemic therapy with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) followed by curative breast surgery at Gangnam Severance Hospital. Patients were excluded from the analysis if they had a history of invasive breast cancer (n = 1), bilateral breast cancer (n = 4), or HER2 amplification confirmed by silver in situ hybridization (SISH) without HER2 protein expression data evaluated by IHC (n = 2). Finally, 348 patients were included in the study (Fig. 1).

We collected clinicopathological data such as age at diagnosis, histologic grade (HG), estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status, TILs, and clinical T and N stage. Clinical T and N stages were evaluated based on pretreatment multimodal imaging studies, including breast magnetic resonance imaging (MRI) and ultrasonography, which were determined according to the anatomical stage based on the 8th American Joint Committee on Cancer guidelines. All pathological data were obtained from core needle biopsy samples before NAST.

Neoadjuvant TCHP therapy was administered via intravenous infusion every 3 weeks for a total of six cycles, per procedure in the TRYPHAENA trial [8]. Docetaxel was administered at 75 mg/m² and carboplatin was administered at an area under the curve of 5 or 6 in all cycles. Trastuzumab was administered at an initial dose of 8 mg/kg on day 1 of cycle 1, followed by a maintenance dose of 6 mg/kg on day 1 of cycles 2–6. Pertuzumab was administered at a loading dose of 840 mg on day 1 of cycle 1, followed by a maintenance dose of 420 mg on day 1 of cycles 2–6.

Immunohistochemistry

IHC staining was performed using a light microscope (BX53upright microscope; Olympus, Tokyo, Japan). Nuclear staining values of 1% or higher were considered positive for ER (clone 6F11; dilution 1:200; Leica Biosystems, Wetzlar, Germany) and PR (clone 16; dilution 1:500; Leica Biosystems) [13]. HER2 staining (clone 4B5; dilution 1:5; Ventana Medical System, Oro Valley, AZ, USA) was performed according to the 2018 American Society of Clinical Oncology/College of American Pathologists [14]. Only samples with a strong circumferential membranous HER2 immunoreactivity (3+) were considered positive, whereas samples with 0 and 1 + HER2 staining were considered negative. Patients with equivocal HER2 expression (2+) were further evaluated for HER2 gene amplification using SISH. Positive nuclear Ki-67 (clone MIB; dilution 1:1000; Abcam, Cambridge, UK) staining was assessed based on the percentage of positive tumor cells, defined as the Ki-67 labeling index.

Of the 348 patients, TILs assessment of core needle biopsy samples were available for 305 patients (87.6%, Fig. 1). Stromal TILs were evaluated in all cores containing invasive cancer cells, according to the guidelines suggested by the International TIL Working Group [15]. Except for polymorphonuclear leukocytes, other mononuclear cells, including lymphocytes and plasma cells, were counted, and the average score was reported as a percentage [16]. For statistical analysis, a 30% cutoff was applied to divide patients into low TIL (< 30%) and high TIL (≥ 30%) groups [17].

Statistical analyses

The objective of this study was to assess the predictive value of HER2 protein expression and TILs evaluated using IHC for treatment response in patients with HER2-positive breast cancer who received neoadjuvant TCHP therapy. We evaluated the pCR rate according to HER2 protein expression and TILs levels stratified by HR status. pCR was defined as no evidence of invasive breast cancer residues in either the breast or the axillary lymph nodes (ypT0/is, ypN0). Categorical variables were compared using the chi-squared test or Fisher’s exact test. Univariate and multivariate analyses were performed using a binary logistic regression model to identify the predictive clinicopathological features of pCR. Odds ratios (OR) and 95% confidence intervals (CI) with two-sided p-values were calculated. All tests were two-sided, and p-values less than 0.05 were considered statistically significant. All statistical analyses were performed using SPSS version 25 software (SPSS, Armonk, NY, USA).

Baseline Characteristics

A total of 348 women with HER2-positive breast cancer who underwent neoadjuvant TCHP followed by curative surgery were identified. The baseline characteristics of the patients are described in Table 1. Age ≥ 50 years was observed in 179 (51.4%) patients, and 158 (45.4%) patients were HR-positive. The majority of patients had HG 1–2 (249 of 304 [86.8%]), clinical T2 or T3 stage (339 of 348 [97.4%]) and were clinically node-positive (279 of 348 [80.2%]).

Table 1. Baseline characteristics according to HER2 expression
Variables	HER2 IHC 2+	HER2 IHC 3+	Total	P value
Age				0.790
< 50	33 (47.1)	136 (48.9)	169 (48.6)
≥ 50	37 (52.9)	142 (51.1)	179 (51.4)
HG				0.238
1 or 2	59 (86.8)	190 (80.5)	249 (81.9)
3	9 (13.2)	46 (19.5)	55 (18.1)
HR				<0.001
positive	54 (77.1)	104 (37.4)	158 (45.4)
negative	16 (22.9)	174 (62.6)	190 (54.6)
TIL levels				0.870
< 30%	41 (61.2)	143 (60.1)	184 (60.3)
≥ 30%	26 (38.8)	95 (39.9)	121 (39.7)
Clinical T stage				0.085
1	2 (2.9)	7 (2.5)	9 (2.6)
2	47 (67.1)	147 (52.9)	194 (55.7)
≥ 3	21 (30.0)	124 (44.6)	145 (41.7)
Clinical N stage				0.768
negative	13 (18.6)	56 (20.1)	69 (19.8)
positive	57 (81.4)	222 (79.9)	279 (80.2)

Note.-Unless otherwise noted, values are the number of patients, with percentages in parentheses.

HER2 = human-epidermal growth receptor factor 2, IHC = immunohistochemistry, HG = histologic grade, HR = hormone receptor, TIL = tumor-infiltrating lymphocyte.

Of the 348 patients, 278 (79.9%) had HER2 IHC 3 + and 70 (20.1%) had HER2 IHC 2+, with HER2 amplification detected using SISH. Patients with HER2 IHC 3 + had a significantly lower proportion of HR-positive tumors than those with HER2 IHC 2+ (37.4% vs. 77.1%, p < 0.001). Compared to patients with HER2 IHC 2+, clinical T3 stage was more frequently observed in patients with HER2 IHC 3+, although the difference was not statistically significant (44.6% vs. 30.0%, p = 0.085). The other characteristics did not differ according to HER2 IHC expression.

TILs in pre-treatment biopsy samples were evaluated in 305 (87.6%) of the 348 patients. Among these patients, 121 (39.7%) had high TIL levels and 184 (60.3%) had low TIL levels (Supplementary Table 1). Patients with high TIL levels were more likely to have high HG (27.1% vs. 12.5%, p = 0.001) and HR-negative status (61.2% vs. 46.2%, p = 0.011) than those with low TIL levels. Meanwhile, the proportion of patients with clinical stage T3 disease was lower in the high TIL level group than in the low TIL level group (29.8% vs. 45.1%, p = 0.026).

Pathologic Complete Response related factors

The overall pCR rate was 65.6% (228 of 348 patients). HER2 IHC expression and TIL levels were significantly associated with pCR. The pCR rate was 71.6% (199 of 278) in the HER2 IHC 3 + group and 34.3% (24 70) in the HER2 IHC 2 + group (p < 0.001; Fig. 2A). In addition, 87 (71.9%) of the 121 patients with high TIL levels achieved pCR, whereas 106 (57.6%) of the 184 patients with low TILs levels achieved pCR (p = 0.011; Fig. 2B). Moreover, the multivariable analysis revealed that HER2 IHC 3+ (OR, 3.66; 95% CI, 1.92–6.96; p < 0.001), high TIL (OR, 1.94; 95% CI, 1.09–3.45; p = 0.024), and HR-negative (OR, 3.33; 95% CI, 1.88–5.91; p < 0.001) were independent predictive factors for pCR (Table 2).

Table 2. Odds ratio (OR) and 95% confidence interval (CI) for pCR in all patients
	Univariable		Multivariable
Variables	OR (95% CI)	P value	OR (95% CI)	P value
Age
< 50	Ref.		Ref.
≥ 50	1.68 (1.08-2.61)	0.022	1.37 (0.80-2.34)	0.256
HG
1 or 2	Ref.		Ref.
3	1.33 (0.71-2.49)	0.369	0.79 (0.38-1.65)	0.531
HR
positive	Ref.		Ref.
negative	3.90 (2.45-6.20)	<0.001	3.33 (1.88-5.91)	<0.001
HER2
IHC 2+	Ref.		Ref.
IHC 3+	4.83 (2.76-8.44)	<0.001	3.66 (1.92-6.96)	<0.001
TIL levels
< 30%	Ref.		Ref.
≥ 30%	1.88 (1.15-3.08)	0.012	1.94 (1.09-3.45)	0.024
Clinical T stage		0.599		0.622
1	Ref.		Ref.
2	0.53 (0.11-2.62)	0.436	0.57 (0.10-3.34)	0.531
≥ 3	0.47 (0.09-2.33)	0.354	0.47 (0.08-2.81)	0.407
Clinical N stage
negative	Ref.		Ref.
positive	0.62 (0.35-1.11)	0.107	0.63 (0.32-1.26)	0.192

pCR = pathologic complete response, HG = histologic grade, HR = hormone receptor, HER2 = human-epidermal growth receptor factor 2, IHC = immunohistochemistry, TIL = tumor-infiltrating lymphocyte.

As HER2 IHC expression and TIL levels differed according to the HR status, we assessed whether the predictive values of HER2 IHC expression and TILs for pCR differed according to the HR status. In patients with HR-negative breast cancer, there was no difference in the pCR rate according to HER2 IHC expression (78.7% [IHC 3+] vs. 68.8% [IHC 2+], p = 0.354; Fig. 3A) and TIL levels (79.7% [IHC 3+] vs. 78.8% [IHC 2+], p = 0.888; Fig. 3B). In contrast, among patients with HR-positive breast cancer, the pCR rate was significantly higher in the HER2 IHC 3 + group than that in the HER2 IHC 2 + group (59.6% vs. 24.1%; p < 0.001; Fig. 3A). Furthermore, pCR was more frequently observed in the high TIL levels group than in the low TIL levels group (59.6% vs. 39.4%, p = 0.022; Fig. 3B). On multivariable analysis, HER2 IHC 3+ (OR, 6.03; 95% CI, 2.60–14.02; p < 0.001) and high TIL levels (OR, 3.23; 95% CI, 1.41–7.40; p = 0.006) remained significant predictors for pCR in HR-positive breast cancer (Table 3).

Table 3

Odds ratio (OR) and 95% confidence interval (CI) for pCR in patients with HR + HER2 + breast cancer
	Univariable		Multivariable
Variables	OR (95% CI)	P value	OR (95% CI)	P value
Age
< 50	Ref.		Ref.
≥ 50	1.32 (0.70–2.49)	0.389	1.83 (0.86–3.89)	0.116
HG
1 or 2	Ref.		Ref.
3	0.86 (0.28–2.61)	0.789	0.69 (0.19–2.49)	0.574
HER2
IHC 2+	Ref.		Ref.
IHC 3+	4.66 (2.23–9.73)	< 0.001	6.03 (2.60-14.02)	< 0.001
TIL levels
< 30%	Ref.		Ref.
≥ 30%	2.27 (1.12–4.60)	0.024	3.23 (1.41–7.40)	0.006
Clinical T stage		0.64		0.935
1	Ref.		Ref.
2	0.54 (0.09–3.36)	0.505	0.82 (0.10–6.50)	0.850
≥ 3	0.69 (0.11–4.42)	0.694	0.91 (0.11–7.67)	0.934
Clinical N stage
negative	Ref.		Ref.
positive	0.96 (0.43–2.15)	0.923	0.84 (0.33–2.13)	0.708
pCR = pathologic complete response, HG = histologic grade, HER2 = human-epidermal growth receptor factor 2, IHC = immunohistochemistry, TILs = tumor-infiltrating lymphocyte.

When the study cohort was classified into four groups according to HR status and HER2 IHC expression, high TIL levels were significantly associated with pCR in the HR-positive, HER2 IHC 3 + group (77.8% vs. 50.8%, p = 0.017, Fig. 4). Additionally, among the HR-positive, HER2 IHC 2 + group, the pCR rate tended to be higher in patients with high TIL levels than in those with low TILs levels, but the difference was not significant (35% vs. 17.6%, p = 0.150).

In this study, we found that HER2 IHC 3 + status and high TIL levels were independent predictors of high pCR rates in patients with HER2-positive breast cancer who underwent neoadjuvant TCHP. Accumulating evidence suggests that the HER2-enriched intrinsic subtype and immune system features are the two most validated predictive biomarkers for HER2-targeted therapy. Previous clinical trials have shown that treatment response to HER2-targeted therapy is higher in the HER2-enriched subtype [18–23]. Similarly, Memorial Sloan Kettering Cancer Center data demonstrated that higher HER2 protein expression levels showed a significant intent to achieve pCR (66% in the HER2 IHC 3 + group vs. 17% in the HER2 IHC 2 + group with confirmed HER2 amplification) [24], probably derived from a higher proportion of HER2-enriched subtype within the HER2 IHC 3 + group. With respect to immune system features, the presence of TILs, programmed death ligand-1 protein expression, T-cell receptor diversity metrics, and immune-related gene signatures are associated with the NAST response [22, 23, 25–27].

Consistent with the previous literature [5, 7, 8], another significant factor related to pCR was HR status; the pCR rate was 77.9% in HR-negative breast cancer and 47.5% in HR-positive breast cancer. However, data on the effects of HER2 protein expression and TILs on pCR rates according to the HR status are limited. Our study revealed that the predictive value of HER2 protein expression and stromal TILs differed according to HR status. HER2 IHC 3 + and high TIL levels were significantly associated with high pCR rates in HR-positive breast cancer. Patients with HR-negative breast cancer achieved an excellent treatment response regardless of HER2 protein expression and TIL levels.

A possible explanation for these findings could be the proportional difference in the HER2-enriched subtype according to the HR status and HER2 protein levels [28]. The HER2-enriched subtype is found in 80–90% of HR-negative and HER2-positive breast cancers and 20–50% of HR-positive and HER2-positive breast cancer [21, 29]. In this study, the majority of patients with HR-negative breast cancer (174 of 190, 91.6%) were HER2 IHC 3+, estimated to be of the HER2-enriched subtype, which may lead to an excellent response to TCHP regardless of TIL levels, considering the mechanisms of trastuzumab and pertuzumab [12]. The lack of difference in the pCR rate between HER2 IHC 2 + and 3 + tumors may imply a strong oncogenic addiction of HER2-positive breast cancer and the efficacy of dual HER2 blockade in HR-negative breast cancer.

Historically, baseline TIL levels have been considered predictor predictor of NAST in HER2-positive breast cancer. However, the predictive role of TILs remains inconclusive when limited to patients receiving NAST-containing trastuzumab and pertuzumab. In exploratory analyses using NeoSphere and TRYPHAENA, immune-related gene signatures were predictive of pCR, but the TILs level itself was not [27, 30]. In the present study, we found that TILs levels were specifically predictive of pCR in HR-positive breast cancer patients treated with neoadjuvant TCHP. Of these, patients with HR-positive breast cancer with HER2 IHC 3 + and high TILs levels exhibited a response rate similar to that of patients with HR-negative, HER2-positive breast cancer. A previous investigation utilizing the PAM50 classification to define the intrinsic subtypes of HER2-positive breast cancer revealed the highest TILs levels in the HER2-enriched subtype [22]. Thus, high HER2 expression and TILs may serve as indicators of the HER2-enriched subtype of HR-positive breast cancer.

Notably, the pCR rate was significantly lower in patients with HR-positive, HER2 IHC 2 + breast cancer, particularly in those with low TIL levels. These patients could be a specific population requiring a new treatment strategy to improve treatment response. Recently, a novel antibody-drug conjugate, trastuzumab deruxtecan, has been approved for the treatment of metastatic HER2-positive breast cancer [31]. Furthermore, trastuzumab deruxtecan is effective in patients with HER2-low (IHC 1 + or 2 + without amplification) breast cancer via the bystander effect [32, 33]. The DESTINY-Breast04 trial showed that trastuzumab deruxtecan had superior therapeutic efficacy compared to standard chemotherapy for HER2-low metastatic breast cancer [34]. Considering that most patients (approximately 89%) enrolled in the DESTINY-Breast04 trial were HR-positive, this new targeted agent could be a promising alternative in patients with HR-positive, HER2 IHC 2 + breast cancer.

Our study had several limitations. First, as this was a retrospective study conducted at a single institution, our results need to be validated in an independent cohort. Second, the number of subpopulations stratified according to HR, HER2 expression, and TILs was relatively small. Only 13 patients had HR-negative, HER2 IHC 2 + breast cancer. Third, we did not perform a genomic analysis that could have elucidated the differences in genomic signatures based on HR status or TILs levels. Finally, the short median follow-up period of our study cohort precluded the investigation of prognostic factors. Despite these limitations, to the best of our knowledge, our study has the strength of exploring predictive clinicopathological factors with the largest number of patients who received homogeneous treatment with platinum-based standard chemotherapy plus trastuzumab and pertuzumab.

In summary, our findings indicate that TCHP has an excellent response in patients with HR-negative, HER2-positive breast cancer, regardless of HER2 protein expression and TILs. Meanwhile, HER2 protein expression and TILs were independent predictors of treatment response in HR-positive breast cancer. Remarkably, among the patients with HR-positive, HER2-positive breast cancer, those with high HER2 expression and high TILs levels exhibited a response rate comparable to patients with HR-negative, HER2-positive breast cancer. However, the remaining subgroup within the HR-positive population derived few benefits from neoadjuvant TCHP, underscoring the need for novel treatment strategies tailored to these specific subpopulations.

Ethics declarations

Conflict of Interest Disclosures

The authors have no conflicts of interest to report.

Funding/Support

This study was supported by a faculty research grant from Yonsei University College of Medicine (6-2019-0109).

Role of the funder/Sponsor

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Author Contributions

Conceptualization: S.J.B., J.H.K., M.J.L., Y.J.C., and J.J.

Data curation, Method: S.J.B., J.H.K., M.J.L., S.H.B., Y.K., S.G.A., Y.J.C., and J.J.

Investigation, Resources: S.J.B., J.H.K., M.J.L., S.H.B., Y.K., S.G.A., Y.J.C., and J.J.

Statistical analysis: S.J.B., J.H.K., M.J.L., Y.J.C., and J.J.

Writing – original draft: S.J.B., J.H.K., M.J.L., Y.J.C., and J.J.

Writing – review & editing: S.J.B., J.H.K., M.J.L., Y.J.C., and J.J.

Availability of data and materials

Joon Jeong, corresponding authors, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis

Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G, Jr., Untch M, Smith I, Gianni L et al: 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017, 389(10075):1195–1205.
Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE, Jr., Martino S, Rastogi P, Gralow J, Swain SM et al: Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol 2014, 32(33):3744–3752.
Killelea BK, Yang VQ, Mougalian S, Horowitz NR, Pusztai L, Chagpar AB, Lannin DR: Neoadjuvant chemotherapy for breast cancer increases the rate of breast conservation: results from the National Cancer Database. J Am Coll Surg 2015, 220(6):1063–1069.
von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A et al: Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019, 380(7):617–628.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P et al: Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014, 384(9938):164–172.
Yau C, Osdoit M, van der Noordaa M, Shad S, Wei J, de Croze D, Hamy AS, Laé M, Reyal F, Sonke GS et al: Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients. Lancet Oncol 2022, 23(1):149–160.
Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012, 13(1):25–32.
Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013, 24(9):2278–2284.
Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H et al: Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 2018, 29(3):646–653.
Loibl S, Jackisch C, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S et al: Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial. Ann Oncol 2017, 28(3):497–504.
van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO, Oving IM, Honkoop AH, Tick LW, van de Wouw AJ et al: Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018, 19(12):1630–1640.
Oh DY, Bang YJ: HER2-targeted therapies - a role beyond breast cancer. Nat Rev Clin Oncol 2020, 17(1):33–48.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M et al: American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010, 28(16):2784–2795.
Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W et al: Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018, 36(20):2105–2122.
Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F et al: The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 2015, 26(2):259–271.
Cha YJ, Ahn SG, Bae SJ, Yoon CI, Seo J, Jung WH, Son EJ, Jeong J: Comparison of tumor-infiltrating lymphocytes of breast cancer in core needle biopsies and resected specimens: a retrospective analysis. Breast Cancer Res Treat 2018, 171(2):295–302.
Loi S, Michiels S, Adams S, Loibl S, Budczies J, Denkert C, Salgado R: The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: clinical utility in an era of checkpoint inhibition. Ann Oncol 2021, 32(10):1236–1244.
Prat A, Bianchini G, Thomas M, Belousov A, Cheang MC, Koehler A, Gómez P, Semiglazov V, Eiermann W, Tjulandin S et al: Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study. Clin Cancer Res 2014, 20(2):511–521.
Fumagalli D, Venet D, Ignatiadis M, Azim HA, Jr., Maetens M, Rothé F, Salgado R, Bradbury I, Pusztai L, Harbeck N et al: RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial. JAMA Oncol 2017, 3(2):227–234.
Pogue-Geile KL, Song N, Jeong JH, Gavin PG, Kim SR, Blackmon NL, Finnigan M, Rastogi P, Fehrenbacher L, Mamounas EP et al: Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J Clin Oncol 2015, 33(12):1340–1347.
Prat A, Pascual T, De Angelis C, Gutierrez C, Llombart-Cussac A, Wang T, Cortés J, Rexer B, Paré L, Forero A et al: HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade. J Natl Cancer Inst 2020, 112(1):46–54.
Dieci MV, Prat A, Tagliafico E, Paré L, Ficarra G, Bisagni G, Piacentini F, Generali DG, Conte P, Guarneri V: Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial. Ann Oncol 2016, 27(10):1867–1873.
Fernandez-Martinez A, Krop IE, Hillman DW, Polley MY, Parker JS, Huebner L, Hoadley KA, Shepherd J, Tolaney S, Henry NL et al: Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer. J Clin Oncol 2020, 38(35):4184–4193.
Krystel-Whittemore M, Xu J, Brogi E, Ventura K, Patil S, Ross DS, Dang C, Robson M, Norton L, Morrow M et al: Pathologic complete response rate according to HER2 detection methods in HER2-positive breast cancer treated with neoadjuvant systemic therapy. Breast Cancer Res Treat 2019, 177(1):61–66.
Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, de Azambuja E, Eidtmann H, Ellis CE, Baselga J et al: Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol 2015, 1(4):448–454.
Barroso-Sousa R, Barry WT, Guo H, Dillon D, Tan YB, Fuhrman K, Osmani W, Getz A, Baltay M, Dang C et al: The immune profile of small HER2-positive breast cancers: a secondary analysis from the APT trial. Ann Oncol 2019, 30(4):575–581.
Bianchini G, Pusztai L, Pienkowski T, Im YH, Bianchi GV, Tseng LM, Liu MC, Lluch A, Galeota E, Magazzù D et al: Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial. Ann Oncol 2015, 26(12):2429–2436.
Prat A, Carey LA, Adamo B, Vidal M, Tabernero J, Cortés J, Parker JS, Perou CM, Baselga J: Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J Natl Cancer Inst 2014, 106(8).
Agostinetto E, Rediti M, Fimereli D, Debien V, Piccart M, Aftimos P, Sotiriou C, de Azambuja E: HER2-Low Breast Cancer: Molecular Characteristics and Prognosis. Cancers (Basel) 2021, 13(11).
Ignatiadis M, Van den Eynden G, Roberto S, Fornili M, Bareche Y, Desmedt C, Rothé F, Maetens M, Venet D, Holgado E et al: Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy: A TRYPHAENA Substudy. J Natl Cancer Inst 2019, 111(1):69–77.
Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF et al: Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med 2022, 386(12):1143–1154.
Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, Soma M, Okamoto H, Oitate M, Arakawa S et al: DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clin Cancer Res 2016, 22(20):5097–5108.
Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T: Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci 2016, 107(7):1039–1046.
Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS et al: Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 2022, 387(1):9–20.

No competing interests reported.

BCRSupplementaryTable.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Predictive markers of treatment response to neoadjuvant systemic therapy with dual HER2-blockade

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Study population

Immunohistochemistry

Statistical analyses

Results

Baseline Characteristics

Pathologic Complete Response related factors

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1