Pathologic complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis

doi:10.21203/rs.3.rs-2731537/v1

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Research Article

Pathologic complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis

https://doi.org/10.21203/rs.3.rs-2731537/v1

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Journal Publication

published 03 Jul, 2023

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Purpose

Ductal carcinoma in situ (DCIS) is present in more than half of HER2-positive invasive breast cancer (IBC). Recent studies show that DCIS accompanying HER2-positive IBC can be completely eradicated by neoadjuvant systemic therapy (NST). Our aim was to determine the percentage of pathologic complete response of the DCIS component in a nationwide cohort and to assess associated clinicopathologic variables. Furthermore, the impact on surgical treatment after NST was investigated.

Methods

Women diagnosed with HER2-positive IBC, treated with NST and surgery, between 2010-2020, were selected from the Netherlands Cancer Registry. Pre-NST biopsy and postoperative specimen pathology reports were obtained from the Dutch Nationwide Pathology Databank, and assessed for presence of DCIS. Clinicopathologic factors associated with DCIS response were assessed using logistic regression analyses.

Results

A DCIS component was present in the pre-NST biopsy in 1443 of the 5834 included patients (24.7%). Pathologic complete response of the DCIS component was achieved in 743 (51.5%) of these patients. Complete response of DCIS occurred more frequently in case of complete response of IBC (63.4% versus 33.8%, p<0.001). ER-negative IBC (OR 1.79; 95%CI 1.33-2.42) and treatment with HER2-targeted therapy (OR 5.97; 95%CI 1.82-19.55) were associated with complete response of DCIS. Mastectomy rates were higher in IBC+DCIS compared to IBC (53.6% versus 41.0%, p<0.001).

Conclusion

Pathologic complete response of DCIS occurred in 51.5% of HER2-positive IBC patients and was associated with ER-negative IBC and complete response of IBC. Future studies should investigate imaging evaluation of DCIS response to improve surgical decision making.

Breast neoplasms

Carcinoma

Intraductal

Noninfiltrating

Neoadjuvant Therapy

Response

Neoadjuvant systemic therapy (NST) has gained an important role in the treatment of invasive breast cancer (IBC). Earlier, NST was reserved for locally advanced or inoperable breast cancer, while nowadays NST can be considered in early stage breast cancer.[6] The main goal of NST is to improve oncologic outcomes and additionally to reduce tumor extent in order to improve breast-conserving surgery rates.[1, 9] The response rate depends on the breast cancer subtype, with the highest rates of pathologic complete response (pCR) in HER2-positive or triple negative IBC.[8]

In case of HER2-positive IBC, a ductal carcinoma in situ (DCIS) component accompanies the invasive tumor in 57.4%-71.6% of patients.[4, 10] Some studies show that in IBC patients with a DCIS component, the pCR rate is lower, while others did not find an association between presence of DCIS and pCR.[11, 18, 20] DCIS was previously considered insensitive to NST, due to its protective basal membrane, less dense micro-vasculature and lower proliferative state as opposed to IBC.[23] Subsequently, IBC patients with a DCIS component were less likely to undergo breast-conserving surgery, both in case of primary surgery and after NST.[10, 22]

Recently, a few studies have shown that the DCIS component accompanying HER2-positive IBC can respond to NST. Von Minckwitz et al. demonstrated that in their population including 59 HER2-positive IBC patients with a DCIS component, 30 (50.8%) showed a pCR of the DCIS component.[20] Groen et al. investigated 138 HER2-positive IBC patients with a DCIS component and showed a pCR of DCIS in 46% of patients after NST. In conclusion, current literature suggests response of the DCIS component in HER2-positive IBC, but these few articles only concerned small study populations.

Therefore, the aim of this study was to determine the rate of pCR of a DCIS component in HER2-positive IBC in a large cohort of patients by performing a nationwide analysis. In addition, the influence of clinicopathologic variables on the rate of pCR of the DCIS component and the impact of the DCIS component on surgical treatment was investigated.

Data sources and study population

A database from the Netherlands Cancer Registry (NCR) was used for this nationwide retrospective study. Since 1989, trained registrars from the Netherlands Comprehensive Cancer Organization (IKNL) have been collecting data regarding patient, tumor, and treatment characteristics of all newly diagnosed cancer patients in the Netherlands. Upon request, the collected data can be used for research after approval by the privacy board of the IKNL.

Women aged 18 years or older, diagnosed with primary HER2-positive IBC, treated with neoadjuvant chemotherapy with or without targeted therapy followed by surgery between January 2010 and December 2019 in the Netherlands, were included from the NCR for the present study. This population was subsequently linked to PALGA, the Dutch Nationwide Pathology Databank.[3] In this way, all pre-NST biopsy and postoperative pathology reports were collected. Patients were excluded in case of missing pre-NST or postoperative pathology reports or when treatment differed from the Dutch guidelines at the year of diagnosis.

Neoadjuvant systemic therapy and surgical procedure

NST consisted of chemotherapy with or without HER2-targeted therapy. Chemotherapy regimens were based on the national guidelines in the year of diagnosis.[12–14] In HER2-positive IBC, NST is recommended in case of tumor size ≥ 5mm or node positive IBC. In case of tumor size ≤2cm NST consisted of weekly Paclitaxel in combination with Trastuzumab for 12 weeks. Patients with a tumor > 2cm or node positive IBC received chemotherapy in combination with targeted therapy. Dual anti-HER2 blockade consisting of Trastuzumab with Pertuzumab was administered from 2017 onwards.

Surgical treatment after NST consisted of breast-conserving surgery or mastectomy and was at the discretion of the treating surgeon in consultation with the patient.

Pathologic assessment of IBC, DCIS and response

Pathologic examination was performed locally according to the Dutch guideline.[12–14] Tumor grade of IBC and the DCIS component was classified according to the modified Bloom-Richardson guideline.[2, 5] Receptor status was evaluated for IBC, not for the DCIS component. ER status was determined using immunohistochemistry and considered positive if ≥ 10% of tumor cells stained positive. HER2 status was examined by immunohistochemistry or in situ hybridization, or in a combination, following ASCO CAP guidelines.[21]

From PALGA, the following information on the DCIS component was collected from the pre-NST biopsy and postoperative pathology reports per patient: the presence of DCIS, tumor grade, and presence of comedonecrosis and/or calcifications.

Patients with a DCIS component present in the pre-NST biopsy were included in the analysis on complete response of DCIS. Complete response was defined as the absence of any DCIS in the postoperative specimen.

Study objectives

Primary endpoint was the percentage of pCR of DCIS in HER2-positive IBC patients with a DCIS component in the pre-NST biopsy. Secondary endpoints were: association between complete response of IBC and complete response of DCIS, association of other clinicopathologic variables with complete response of DCIS, and impact of the presence of a DCIS component pre-NST on surgical treatment after NST.

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, version 26, Armonk, New York). Descriptive statistics were used to summarize the study population. Complete response of the DCIS component was calculated as percentage of the patients with IBC + DCIS in the pre-NST biopsy. Pearson’s χ² test was used to compare IBC response with DCIS response, and in this analysis IBC response was defined as absence of invasive breast cancer after NST (ypT0/is). Clinicopathologic variables associated with complete response of DCIS were determined by univariable logistic regression analyses. Subsequently, multivariable logistic regression analyses were performed to adjust for potential confounders. Surgical treatment was compared between patients with IBC + DCIS and patients with pure IBC in the pre-NST biopsy using Pearson’s χ² test. A p-value ≤ 0.05 was considered statistically significant.

In the period of 2010-2020, 6380 women with HER2-positive IBC received NST followed by surgical treatment in the Netherlands. After exclusion of ineligible patients (n=546), 5834 patients were included in the study population (Figure 1). Subsequently, pathology reports were assessed for the presence of DCIS and 1443 patients (24.7%) showed a DCIS component in the pre-NST biopsy. These patients were included in the analysis on pathologic complete response of the DCIS component. The other 4391 patients (75.3%) did not show a DCIS component in the pre-NST biopsy and were excluded from further analyses on DCIS response. An overview of the patient inclusion and classification based on pathology reports is shown in Figure 1.

Patient characteristics

Baseline characteristics of the 1443 patients with IBC+DCIS are shown in Table 1. Patients were most commonly diagnosed with cT2 tumor (50.6%), ER-positive (63.1%) and morphology of invasive carcinoma no special type (92.0%). IBC grade was most commonly grade 3 (48.7%), followed by grade 2 (46.1%). In this HER2-positive IBC cohort, 97.2% was treated with chemotherapy in combination with targeted therapy and the other 2.8% with chemotherapy only. Patients with clinical tumor status Tis (n=8) were included in the study population, since they had clinically node positive disease and were treated with NST. Patients were classified as cTX (n=18) when IBC was detected in pre-NST biopsy but cT status could not be determined on imaging.

Histopathologic characteristics of the DCIS component in the pre-NST biopsies are also shown in Table 1. Comedonecrosis and calcifications were present in 534 (77.2%) and 468 (61.7%) patients, respectively. The DCIS component was most often grade 3 (n=733, 62.6%). DCIS grade and IBC grade were concordant in 62.1% of patients (547/881 patients, Supplementary Table 1).

Table 1 Baseline characteristics of patients with IBC with a DCIS component

Characteristics	IBC + DCIS (n=1443) N (%)
Age at diagnosis in years, median [range]	48 [22-84]
Clinical tumor status
T1	266 (18.5)
T2	729 (50.6)
T3	334 (23.1)
T4	86 (6.0)
Tis^a	8 (0.6)
TX^a	18 (1.2)
Missing	2
Clinical nodal status
N0	631 (44.0)
N1	630 (43.9)
N2-3	173 (12.1)
Missing	9
IBC morphology
Invasive carcinoma of no special type	1327 (92.0)
Lobular	5 (0.3)
Other	111 (7.7)
IBC grade
1	54 (5.2)
2	476 (46.1)
3	503 (48.7)
Missing	9
IBC ER status
ER-positive	909 (63.1)
ER-negative	532 (36.9)
Missing	2
DCIS grade
1	34 (2.9)
2	404 (34.5)
3	733 (62.6)
Missing	272
Comedonecrosis
Present	534 (77.2)
Absent	158 (22.8)
Missing	751
Calcifications
Present	468 (61.7)
Absent	290 (38.3)
Missing	685
NST
Chemotherapy	40 (2.8)
Chemotherapy + targeted therapy	1403 (97.2)

^aDiagnosed with cN+ disease and treated with NST

Association between clinicopathologic variables and the complete response of DCIS to NST

As presented in Figure 1, 51.5% of the patients with a DCIS component in the pre-NST biopsy showed pCR of the DCIS component. The number of patients with complete response of the invasive tumor (ypT0/is) in comparison to complete response of the DCIS component is shown in Table 2. Complete response of the DCIS component occurred significantly more often in case of complete response of the invasive tumor compared to patients with residual IBC (63.4% versus 33.8%, p<0.001).

Table 2 Comparison of complete pathologic response of IBC and the DCIS component in the postoperative specimen after NST

No. (%) Total n=1443	Complete response of DCIS	Residual DCIS	p value
	n = 743/1443 (51.5%)	n = 699/1443 (48.5%)
Complete response of IBC	548/865 (63.4%)	317/865 (36.6%)	<0.001^a
n = 865/1443 (60.0%)
Residual IBC	195/577 (33.8%)	382/577 (66.2%)
n = 577/1443 (40.0%)

^a = statistically significant

The univariable and multivariable logistic regression analyses for clinicopathologic variables associated with complete response of DCIS are shown in Table 3. In univariable analyses, age at diagnosis above 50 (OR 1.44; 95% CI 1.17-1.78), clinical tumor status T3 (OR 0.58; 95% CI 0.42-0.80), ER-negative IBC (OR 1.67; 95% CI 1.34-2.07) and treatment with chemotherapy in combination with HER2-targeted therapy (OR 2.25; 95% CI 1.15-4.40) were significantly associated with complete DCIS response. Of the pathologic characteristics of the DCIS component, presence of both comedonecrosis (OR 0.66; 95% CI 0.46-0.95) and calcifications (OR 0.58; 95% CI 0.43-0.78) were significantly associated with a complete response of DCIS to NST. DCIS grade and IBC grade were not associated with DCIS response.

In multivariable logistic regression analyses, ER-negative IBC (OR 1.80; 95% CI 1.34-2.43) and treatment with chemotherapy in combination with HER2-targeted therapy (OR 5.49; 95% CI 1.75-17.20) were independently associated with higher odds for pCR of the DCIS component. Clinical tumor status T3 was independently associated with lower odds for pCR of the DCIS component (OR 0.59; 95% CI 0.39-0.90). The other abovementioned univariable clinicopathologic variables did not reach significance after multivariable logistic regression analysis. Comedonecrosis and calcifications were not included in the multivariable logistic regression analysis because of high numbers of missing data, resulting in too many patients being excluded from the analysis.

Table 3 Association of clinicopathologic variables with complete response of DCIS to NST in univariable and multivariable regression analyses

	Complete pathologic response of DCIS N/total (%)	Univariable analysis			Multivariable analysis
Clinicopathologic factors		OR	95% CI	p value	OR	95% CI	p value
Age at diagnosis (years)
<50	388/816 (47.5%)	REF			REF
≥50	355/627 (56.6%)	1.44	1.17 – 1.78	0.001^a	1.297	0.98 – 1.71	0.07
Clinical tumor status
T1	152/266 (57.1%)	REF			REF
T2	381/729 (52.3%)	0.82	0.62 – 1.09	0.17	0.82	0.57 – 1.17	0.27
T3	145/334 (43.4%)	0.58	0.42 – 0.80	0.001^a	0.59	0.39 – 0.90	0.02^a
T4	51/86 (59.3%)	1.09	0.67 – 1.79	0.73	1.28	0.61 – 2.69	0.51
Tis^b	4/8 (50.0%)	0.75	0.18 – 3.06	0.69	1.31	0.12 – 14.85	0.83
TX^b	9/18 (50.0%)	0.75	0.29 – 1.95	0.56	1.55	0.27 – 8.82	0.62
IBC grade
Grade 1	29/54 (53.7%)	REF			REF
Grade 2	247/476 (51.9%)	0.93	0.53 – 1.64	0.80	0.74	0.38 – 1.43	0.74
Grade 3	273/503 (54.3%)	1.02	0.58 – 1.80	0.94	0.78	0.40 – 1.52	0.78
ER status
Positive	425/909 (46.8%)	REF			REF
Negative	316/532 (59.4%)	1.67	1.34 – 2.07	<0.001^a	1.80	1.34 – 2.43	<0.001^a
DCIS grade
1	15/34 (44.1%)	REF			REF
2	218/404 (54.0%)	1.49	0.73 – 3.00	0.27	1.48	0.65 – 3.39	0.35
3	379/733 (51.7%)	1.36	0.68 – 2.71	0.39	1.20	0.53 – 2.75	0.66
Comedonecrosis
Absent	95/158 (60.1%)	REF			^c
Present	267/534 (50.0%)	0.66	0.46 – 0.95	0.03^a	^c
Calcifications
Absent	173/290 (59.7%)	REF			^c
Present	216/468 (46.2%)	0.58	0.43 – 0.78	<0.001^a	^c
NST
Chemotherapy	13/40 (32.5%)	REF			REF
Chemotherapy + HER2 targeted therapy	730/1403 (52.0%)	2.25	1.15 – 4.40	0.02^a	5.49	1.75 – 17.20	0.003^a

^a = statistically significant, ^b = diagnosed with cN+ disease and treated with NST, ^c = comedonecrosis and calcifications were not included in multivariable analysis due to high number of missing values

Abbreviations: OR odds ratio

Surgical treatment after NST

Surgical treatment differed significantly between patients with IBC+DCIS (n=1443) and patients with pure IBC (n=4391) in the pre-NST biopsy. Mastectomy was more often performed as primary surgical treatment in patients with IBC+DCIS (n=773, 53.6%) compared to pure IBC (n=1802, 41.0%) (p<0.001). Of the total of 2575 patients receiving primary mastectomy, 1041 (40.4%) showed complete response (ypT0) in the postoperative pathology specimen (Supplementary Table 2).

In current studies investigating response to NST in breast cancer treatment, only a few studies have been conducted on the pathologic response of DCIS to NST. To the best of our knowledge, this is the first nationwide analysis investigating a large cohort of HER2-positive IBC patients with a DCIS component, and a pCR of DCIS was found in 51.5% of 1443 patients. In addition, we demonstrated that pCR of the DCIS component was associated with complete response of IBC, ER negativity of IBC and treatment with targeted therapy. Patients with a DCIS component in the pre-NST biopsy were significantly more often treated with mastectomy after NST compared to patients without a DCIS component.

The rate of pCR of the DCIS component is consistent with the outcomes of previous, smaller studies. Groen et al. and von Minckwitz et al. investigated the response of a DCIS component in HER2-positive IBC patients and found a complete response in 46% and 51% of these patients, respectively.[7, 20] Sun et al. found a slightly lower response rate of 35.7% in their population of 129 HER2-postive IBC patients.[18] Goldberg et al. investigated the response of a DCIS component in IBC patients treated with NST and found a response rate of 33%. This lower response rate can be explained by the study population consisting of different IBC subtypes, including HER2-negative. In comparison to these previous studies, a significantly larger number of patients was included in our study. Therefore, this study may be seen as a confirmation of previous results.

In addition, the potential association between clinicopathologic variables and DCIS response was investigated. First, it was found that complete response of the DCIS component occurred significantly more often in case of complete response of the invasive tumor (63.4% versus 33.8%, p<0.001). Previous studies show a high concordance in receptor status and grade between the invasive tumor and the accompanying DCIS component.[15-17] In our multivariable analysis, ER-negative IBC and treatment with targeted therapy were found to be significantly associated with complete response of DCIS. These variables are also associated with higher invasive tumor response in previous studies.[8, 19] Given that IBC and the accompanying DCIS are comparable, their response could be affected by the same factors.[15-17]

One previous study investigated the relation of clinicopathologic factors and DCIS response. Groen et al. found that dual HER2-blockade, absence of calcifications in the biopsy and on mammography, and (near) complete radiologic response on breast MRI were independently associated with DCIS response.[7] In our univariable analysis, absence of calcifications in the pre-NST biopsy was also associated with complete response of DCIS. Our database did not include information on treatment with single or dual anti-HER2 blockade and imaging findings.

This study has strengths and limitations. A strength is the nationwide database that allowed for evaluation of DCIS response on a large scale, in comparison to previous smaller study populations. Second, various clinicopathologic variables were taken into consideration, which enabled evaluation of association between clinicopathologic variables and complete response of the DCIS component.

There are certain limitations worth mentioning. First, due to the retrospective nature of our database, some variables are missing because of insufficient reporting. Unfortunately, until now the presence and characteristics of a DCIS component is not a mandatory field in completing the Dutch pathology module. This could lead to reporting bias by the pathologist focusing on the invasive tumor. Moreover, the receptor status of the DCIS component is not yet a standard determination and could therefore not be investigated in relation to response.

Second, the pre-NST biopsy collection generates another limitation. Since DCIS can appear outside of the area of the invasive tumor, there may be a risk of missing the DCIS component, when targeting the invasive tumor during biopsy. The presence of a DCIS component can therefore be underestimated and this may affect the complete response rate. Moreover, the location and size of the DCIS component outside of the invasive tumor can influence the possibility to perform breast-conserving surgery, but this was not possible to investigate based on the pre-NST pathology reports. Lastly, the higher mastectomy rate in the patients with a DCIS component could not be further evaluated because our database did not include relevant additional data (e.g. gene expression, extent of mammographic calcifications, patients’ preference regarding surgical treatment).

Further research into complete response of DCIS in HER2-positive IBC is important, because our study confirms the increased mastectomy rate found in previous studies in patients with IBC+DCIS versus patients without a DCIS component (53.6% versus 41.0%, p<0.001).[10, 22] In order to implement the potential response of the DCIS component in personalizing surgical treatment after NST, future studies should evaluate whether it is possible to monitor response of the DCIS component by imaging modalities. Moreover, a thorough investigation of pathologic characteristics of the DCIS component in relation to response could be useful to predict DCIS response before start of NST.

In conclusion, in this nationwide retrospective study, we demonstrated that pCR of DCIS to NST occurred in 51.5% of the HER2-positive IBC patients with a DCIS component in pre-NST biopsy. Therefore, the presence of a DCIS component in particular should not necessarily indicate the need for mastectomy, especially in ER-negative HER2-positive IBC patients with complete response of the invasive tumor. Future studies should investigate the evaluation of DCIS response by imaging and the possibility of increasing the chance of breast-conserving surgery.

Acknowledgments

The authors gratefully thank the registration team of the Netherlands Comprehensive Cancer Organization for the collection of the data for the NCR. Furthermore, the authors gratefully thank the Dutch Nationwide Pathology Databank (PALGA) for providing the histopathologic data.

Funding

For this study, R. Ploumen received a grant from the Jules Coenegracht Senior Foundation (Maastricht, the Netherlands). The funder had no role in the conceptualization, data collection, analysis, interpretation, or writing.

Competing interests

The authors declare the following financial interests/personal relationships:

Prof. Dr. Smidt reports grants from Nutricia and Servier Pharmaceuticals for microbiome research in colorectal cancer, not related to this study. Dr. T. van Nijnatten received institutional grant support from Bayer, and speaker honoraria from GE Healthcare and Bayer, not related to this study. L. Kooreman reports consulting fees from Novartis and educational fees from SCEM, not related to this study.

All other authors declare no conflicts of interest.

Author contributions

Ploumen, Kooreman, van Nijnatten and Smidt contributed to the study conception and design. Data acquisition and collection were performed by Ploumen, van Nijnatten, Smidt and Siesling. Data interpretation and (statistical) analysis were performed by Ploumen, Claassens, Kooreman, van Kats, Siesling, van Nijnatten and Smidt. The first draft was written by Ploumen and Claassens, whereafter all authors provided feedback on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability Statement

The data used for this retrospective study were obtained via The Netherlands Comprehensive Cancer Organization (IKNL) from the Netherlands Cancer Registry. This specific dataset is generated for the current study by the registration team of IKNL after permission by their privacy board. Therefore, restrictions apply to the availability of the data and this specific dataset is not publicly available. However, the data are available upon reasonable request and with permission of the IKNL.

Ethics Approval

The current study was approved by the institutional ethics and privacy committee of The Netherlands Comprehensive Cancer Organization (IKNL) after reviewing the study protocol.

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Pathologic complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis

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Introduction

Materials And Methods

Data sources and study population

Neoadjuvant systemic therapy and surgical procedure

Pathologic assessment of IBC, DCIS and response

Study objectives

Statistical analysis

Results

Discussion

Declarations

References

Status:

Journal Publication

Version 1