Evaluating the risk of underdiagnosis of invasive breast cancer in needle biopsy-diagnosed ductal carcinoma in situ eligible for radiofrequency ablation

doi:10.21203/rs.3.rs-4866912/v1

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Research Article

Evaluating the risk of underdiagnosis of invasive breast cancer in needle biopsy-diagnosed ductal carcinoma in situ eligible for radiofrequency ablation

https://doi.org/10.21203/rs.3.rs-4866912/v1

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Background

Radiofrequency ablation (RFA) is considered a promising alternative to surgical excision for patients with small, unifocal early-stage breast cancer. A significant concern with the application of RFA in patients diagnosed with ductal carcinoma in situ (DCIS) via needle biopsy is the underdiagnosis of invasive cancer. The extent of this underdiagnosis in DCIS patients eligible for RFA has not been clearly defined.

Methods

This retrospective study assessed lesions diagnosed as DCIS via needle biopsy and eligible for RFA at our institution from April 2009 to March 2024. The eligibility criteria for RFA included a lesion size of ≤ 1.5 cm, unifocality, and clinical node negativity. Underdiagnosis was defined as the presence of invasive cancer in surgical specimens. We evaluated the frequency and risk factors associated with underdiagnosis.

Results

During the study period, 606 lesions were diagnosed as DCIS via needle biopsy. Of these, 209 lesions met the criteria for RFA, with underdiagnosis determined in 40 lesions (19.1%). The distribution of pathological T (pT) stages among these lesions was as follows: DCIS in 169 lesions (80.9%), pT1mi in 20 lesions (9.6%), pT1a in 5 lesions (2.4%), pT1b in 9 lesions (4.3%), pT1c in 5 lesions (2.4%), and pT2 in 1 lesion (0.5%). Multivariate logistic regression analysis identified lesion size ≥ 10 mm as a significant risk factor for underdiagnosis (p = 0.016). Adjuvant endocrine therapy and chemotherapy were administered to 26 (65.0%) and 6 (15.0%) of the underdiagnosed lesions, respectively.

Conclusions

Our findings highlight the risk of underdiagnosing invasive breast cancer in patients undergoing RFA for needle biopsy-diagnosed DCIS. It is crucial to acknowledge the potential for undertreatment when considering RFA as a treatment option.

Radiofrequency ablation

DCIS

needle biopsy

underdiagnosis

The detection rate of early-stage breast cancer has increased with the introduction of mammography screening. The proportion of ductal carcinoma in situ (DCIS) was approximately 20% in screen-detected breast cancer [1, 2]. Breast conserving surgery has become the standard treatment for early breast cancer, including DCIS [3, 4]. However, surgical excision decreases quality of life because it is invasive, causes postoperative pain, and reduces cosmetic outcomes [5]. Therefore, nonsurgical treatments for small early-stage breast cancers that achieve good cosmetic outcomes are under investigation [6–10].

The RAFAELO trial, a single-arm validation study, demonstrated extremely high ipsilateral breast recurrence-free survival rates using radiofrequency ablation (RFA) for early-stage breast cancer with tumor diameters of ≤ 1.5 cm, without axillary lymph node or distant metastasis [11]. RFA can be a promising alternative to surgical excision in early breast cancer that meets eligibility criteria.

Compared to surgical resection, RFA lacks surgical pathological findings. A certain proportion of needle biopsy-diagnosed DCIS was found to have invasive cancer on the surgical specimen, indicating underdiagnosis of invasive cancer [12]. In needle biopsy-diagnosed DCIS with underdiagnosis, inadequate adjuvant therapy may lead to poorer long-term prognosis in patients treated with ablation [13]. However, no study has specified the frequency of underdiagnosis in biopsy-diagnosed DCIS meeting the eligibility criteria for RFA.

In this retrospective observational study, we evaluated the frequency and risk factors for underdiagnosis in needle biopsy-diagnosed DCIS meeting the eligibility criteria for nonsurgical ablation as follows: 1) lesion size of ≤ 1.5 cm, 2) single lesion, 3) and clinical node negativity.

Study design

This study was approved by the Ethical Committee for Epidemiology of Hiroshima University (no. E2018-1166) and conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical Research Involving Human Subjects. Given the retrospective observational design of the trial, the requirement for patient written consent was waived. The study included patients with breast cancer diagnosed as DCIS by needle biopsy at the Department of Breast Surgery, Hiroshima University Hospital, from April 2009 to March 2024. In accordance with the eligibility criteria used for other trials on RFA for early breast cancer [6, 7], this study evaluated lesions that met the following criteria:

Diagnosed as DCIS via needle biopsy
Lesion size of ≤ 1.5 cm in preoperative imaging tests
Single lesion
Without axillary lymph node metastasis (cN0) and distant metastasis (cM0)
Surgical resection of breast lesion with pathological findings

During this period, 606 lesions were diagnosed as DCIS by needle biopsy. Of these, 357 lesions had a lesion size of > 1.5 cm, 26 were multicentric, 6 were cN+, and 8 did not receive surgical resection. Finally, 209 lesions were included in this study (Fig. 1).

Clinicopathological factors

We evaluated clinical and pathological factors as follows: age at diagnosis, sex, menopausal status, presence of mass lesions on imaging, microcalcifications on mammography, lesion palpability, lesion size, needle biopsy procedure, nuclear grade, estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor 2 (HER2). Lesion size was determined based on imaging findings. Needle biopsy procedure was categorized into core needle biopsy or vacuum-assisted biopsy under the physician’s directions. ER and PgR were assessed by immunohistochemistry, with ≥ 1% considered positive [14]. ER or PgR positivity was considered hormone receptor (HR) positive. HER2 status was assessed using immunohistochemistry, with 3 + classified as positive and 0, 1+, and 2 + as negative [15]. Fluorescence in situ hybridization was not performed for HER2 + lesions because this study involved needle biopsy-diagnosed DCIS. The nuclear grade classification of DCIS was categorized into low, intermediate, and high according to the consensus classification [16]. Presence of invasive disease, pT, and pN were evaluated in surgical specimens. pT and pN were evaluated according to the TNM classification [17]. Underdiagnosis of needle biopsy in the surgical specimens was defined as the identification of invasive disease, including microinvasive carcinoma. The rates of underdiagnosis and distribution of pT and pN were evaluated. After curative surgery, adjuvant chemotherapy and endocrine therapy were administered according to the National Comprehensive Cancer Network guidelines and St. Gallen consensus [13]. These clinicopathological findings were obtained from a prospectively maintained hospital database.

Statistical analysis

To identify predictors of underdiagnosis, the relationship between underdiagnosis and clinicopathological factors was evaluated using logistic regression analysis. Significant factors in a univariate analysis (p < 0.05) were evaluated in a multivariate analysis. Odds ratios and 95% confidence interval were calculated for significant factors in the multivariate analysis. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed using JMP software (version 13.2.1, SAS Institute Inc., Cary, USA).

Patient characteristics

Patient demographics are shown in Table 1. Median age at diagnosis was 60 years, with an interquartile range of 49–69. All patients were female. Mass-forming lesions were found in 121 (57.9%) cases. Microcalcifications on mammography were present in 93 (44.5%) lesions. Palpable lesions were reported in 46 (22%) cases. Median lesion size was 8 mm, with an interquartile range of 6–12 mm, and lesions of > 10 mm were seen in 80 (38.3%) cases. Needle biopsies were conducted using core needle biopsy in 129 (61.7%) and vacuum-assisted biopsy in 80 (38.3%) lesions. Nuclear grading identified 92 low-grade (44.0%), 86 intermediate-grade (41.1%), and 31 high grade (14.8%) lesions. ER, PgR, and HER2 were positive in 180 (86.1%), 166 (79.4%), and 26 (12.6%) lesions, respectively, with statuses of HR-positive/HER2-negative in 160 (76.6%), HER2-positive in 26 (12.5%), and HR-negative/HER2-negative in 16 (7.7%) lesions. Breast conserving surgery and mastectomy were performed in 149 and 60 patients, respectively. Sentinel lymph node biopsy was performed for axillary staging in 156 patients, with axillary surgery omitted in 53. Adjuvant systemic therapies included chemotherapy in 9 (4.3%) and hormone therapy in 45 (21.5%) patients.

Table 1

Clinicopathological characteristics
Variables		Number of breast cancer (%)
Age
	Median 60 (IQR: 49–69)
	≥ 56	116 (55.6)
	55≥	93 (44.5)
Sex
	Female	209 (100)
Menopausal status
	Premenopausal	77 (36.8)
	Postmenopausal	132 (63.1)
Mass formation
	Mass	121 (57.9)
	Non-mass lesion	88 (42.1)
Microcalcification on mammography
	Yes	93 (44.5)
	No	116 (55.5)
Palpability
	Yes	46 (22.0)
	No	163 (78.0)
Clinical lesion size (mm)
	Median 8 (IQR: 6–12)
	0-9.9	125 (59.8)
	10–15	84 (40.2)
Needle biopsy method
	Core needle biopsy	129 (61.7)
	Vacuum-assisted biopsy	80 (38.3)
Grade
	Low	92 (44.0)
	Intermediate	86 (41.1)
	High	31 (14.8)
Estrogen receptor
	Positive	180 (86.1)
	Negative	24 (11.4)
	Unknown	5 (2.4)
Progesterone receptor
	Positive	166 (79.4)
	Negative	38 (18.2)
	Unknown	5 (2.4)
HER2
	Positive	26 (12.6)
	Negative	176 (85.0)
	Unknown	7 (3.3)
Subtype
	HR + HER2-	160 (76.6)
	HER2+	26 (12.5)
	HR-HER2-	16 (7.7)
	Unknown	7 (3.3)
Breast Surgery
	Breast conserving surgery	149 (71.3)
	Mastectomy	60 (28.7)
Axillary surgery
	No	53 (25.4)
	Sentinel lymph node biopsy	156 (74.6)
pT
	DCIS	169 (80.9)
	Invasion	40 (19.1)
	T1mi	20 (9.6)
	T1a	5 (2.4)
	T1b	9 (4.3)
	T1c	5 (2.4)
	T2	1 (0.5)
pN
	N0	207 (99.0)
	N1	1 (0.5)
	N2	1 (0.5)
Adjuvant endocrine therapy
	Yes	45 (21.5)
	No	164 (78.5)
Adjuvant chemotherapy
	Yes	6 (4.3)
	No	200 (95.7)
IQR, interquartile range; HER2, human epidermal growth factor receptor 2

Frequency of underdiagnosis

Table 1 shows the pathological findings in surgical specimens and adjuvant therapy. Invasive carcinoma was observed in 40/206 (19.1%) lesions. pT stage distribution was as follows: DCIS in 169 (80.9%), pT1mi in 20 (9.6%), pT1a in 5 (2.4%), pT1b in 9 (4.3%), pT1c in 5 (2.4%), and pT2 in 1 (0.5%) lesion. Figure 2 shows the distribution of pT stages in surgical specimens according to HR and HER2 status. In HR-positive/HER2-negative lesions, invasive cancer was found in 33 (20.6%) lesions, with T1b or higher in 12 (7.5%) lesions. In HER2-positive lesions, invasive cancer was present in 5 (19.2%) lesions, and T1b or higher in 1 (6.3%) lesion. For HR-negative/HER2-negative lesions, both invasive cancer and T1b or higher were recorded in 2 (12.5%) lesions. Lymph node metastases were found in 2 (1.0%) lesions, including pN1 in 1 (0.5%) and pN2 in 1 (0.5%) lesion.

Predictors of underdiagnosis

The association between underdiagnosis and clinicopathological factors is shown in Table 2. In univariate analysis, lesion size, both as a categorical and continuous variable, along with palpability, were significantly associated with underdiagnosis. Age (p = 0.67), mass-forming lesion (p = 0.51), calcification on mammography (p = 0.32), type of needle biopsy (p = 0.12), grade (p = 0.60), ER (p = 0.36), PgR (p = 0.84), and HER2 (p = 0.96) were not significant predictors. In multivariate analysis, lesion size as a categorical variable (odds ratio: 2.42 and 95% confidence interval: 1.17–5.00; p = 0.017) was significantly correlated with underdiagnosis.

Table 2

Association between clinicopathological factors and underdiagnosis in univariate and multivariate analyses
			Surgical specimens		Univariate analysis			Multivariate analysis
Variable		Total (%)	Invasive breast cancer (%)	DCIS (%)	OR	95% CI	p value	OR	95% CI	p value
Age
	≥ 56	93 (44.5)	19 (20.4)	74 (79.6)	0.86	0.43–1.7	0.67
	55≥	116 (55.5)	21 (18.1)	95 (81.9)
Mass formation
	Mass	121 (57.9)	25 (20.7)	96 (79.3)	1.26	0.62–2.57	0.51
	Non-mass lesion	88 (42.1)	15 (17.1)	73 (82.9)
Microcalcification on mammography
	Yes	93 (44.5)	25 (21.6)	68 (78.4)	0.70	0.34–1.40	0.32
	No	116 (55.5)	15 (16.1)	101 (83.9)
Palpability
	Yes	46 (22.0)	14 (30.4)	32 (69.6)	2.31	1.08–4.91	0.030	1.87	0.85–4.08	0.13
	No	163 (78.0)	26 (16.0)	137 (84.0)
Clinical lesion size (mm)
	≥ 10	84 (40.2)	24 (28.6)	60 (71.4)	2.73	1.34–5.52	0.005	2.42	1.17-5.00	0.016
	< 10	125 (59.8)	16 (12.8)	109 (87.4)
Needle biopsy procedure
	Core needle biopsy	129 (61.7)	29 (22.5)	100 (77.5)	1.82	0.85–3.89	0.12
	Vacuum-assisted biopsy	80 (38.3)	11 (13.8)	69 (86.2)
Grade
	low, mediate	178 (85.2)	33 (18.5)	145 (81.5)	1.28	0.51–3.23	0.60
	high	31 (14.8)	7 (22.6)	24 (77.4)
Estrogen receptor
	Positive	180 (86.1)	37 (20.1)	143 (79.9)	1.81	0.51–5.40	0.36
	Negative	24 (11.5)	3 (12.5)	21 (87.5)
Progesterone receptor
	Positive	166 (79.4)	33 (19.9)	133 (80.1)	1.10	0.44–2.71	0.84
	Negative	38 (18.2)	7 (18.4)	31 (81.69
HER2
	Positive	26 (12.4)	5 (19.2)	21 (80.8)	0.96	0.34–2.72	0.94
	Negative	176 (84.2)	35 (19.9)	141 (80.1)
OR, odds ratio; CI, confidence interval; HER2, human epidermal growth factor receptor 2

pT stage distribution and adjuvant systemic therapy in underdiagnosed lesions

Table 3 shows the pT distribution and adjuvant systemic therapy in the 40 lesions with underdiagnosis. pT1mi, T1a, T1b, T1c, and T2 were identified in 20 (50.0%), 5 (12.5%), 9 (22.5%), 5 (12.5%), and 1 (2.5%) lesion, respectively. Consequently, T1b or higher was observed in 15 (37.5%) cases. Adjuvant endocrine therapy and chemotherapy were administered to 26 (65.0%) and 6 (15.0%) lesions, respectively.

Table 3

Pathological findings and adjuvant systemic therapy in underdiagnosed lesions
Variable		Number of breast cancer (%)
Total		40 (100)
Estrogen receptor
	Positive	37 (92.5)
	Negative	3 (7.5)
Progesterone receptor
	Positive	33 (82.5)
	Negative	7 (17.5)
HER2
	Positive	35 (87.5)
	Negative	5 (12.5)
Subtype
	HR + HER2-	33 (82.5)
	HER2+	5 (12.5)
	HR-HER2-	2 (5.0)
pT
	T1mi	20 (50.0)
	T1a	5 (12.5)
	T1b	9 (22.5)
	T1c	5 (12.5)
	T2	1 (2.5)
pN
	N0	38 (95.0)
	N1	1 (2.5)
	N2	1 (2.5)
Adjuvant endocrine therapy
	Yes	26 (65.0)
	No	14 (35.0)
Adjuvant chemotherapy
	Yes	6 (15.0)
	No	34 (85.0)

This retrospective observational study assessed the underdiagnosis of invasive cancer in needle biopsy-diagnosed DCIS meeting eligibility criteria for RFA. Among the 209 DCIS in needle biopsy specimens, invasive cancer was detected in 40 (19.1%) lesions and a lesion size of ≥ 10mm was a significant factor for underdiagnosis. Of the 40 underdiagnosed lesions, ≥T1b was observed in 15 (37.5%) and adjuvant endocrine therapy and chemotherapy were administered for 26 (65.0%) and 6 (15.0%) lesions, respectively.

A meta-analysis assessed the frequency and predictors of invasive breast cancer underdiagnosis in lesions initially diagnosed as DCIS through needle biopsy [12]. Approximately 25% of these cases were underdiagnosed. Preoperative factors significantly associated with underdiagnosis included biopsy device and guidance method, lesion size and grade, mammographic features, and lesion palpability. Predictive models and machine learning have been developed to identify underdiagnosis [18–21], and clinical trials on active surveillance for low-risk breast cancer diagnosed as DCIS through needle biopsy are in progress [22–25]. However, a comprehensive review and external validation of these predictive models highlighted the lack of consensus regarding predictors for underdiagnosis and use in daily practice [26]. The frequency of underdiagnosis in needle biopsy-diagnosed DCIS eligible for active surveillance trials was 4–25% [27–29]. These findings indicate that accurately diagnosing DCIS preoperatively is challenging, and that a certain number of underdiagnosed cases exist in needle biopsy-diagnosed DCIS.

In the RAFAELO trial, a single-arm validation study, RFA achieved excellent local control, with a five-year ipsilateral breast recurrence rate of 0.57% in 353 participants [11]. The RAFAELO trial enrolled women with solitary localized lesions of ≤ 1.5 cm without axillary lymph node or distant metastases. Invasive ductal carcinoma and DCIS accounted for 87.0% and 11.3% of the cases, respectively. One drawback of RFA therapy is the lack of surgical pathology findings. Although all eligibility criteria for RFA were considered low-risk factors for underdiagnosis, 19.1% of the needle biopsy-diagnosed DCIS cases meeting these criteria were underdiagnosed in this study. The incidence of underdiagnosis can be attributed to including DCIS with risk factors for underdiagnosis, such as high grade, mass formation, and lesion palpability. Additionally, 50% of the underdiagnosed lesions in this study were T1mi. The higher proportion of microinvasive cancers than previously reported may have influenced the observed frequency [30, 31]. By contrast, lymph node metastasis was rare in this study, consistent with earlier findings [32, 33]. Axillary staging is deemed unnecessary for needle biopsy-diagnosed DCIS that meets RFA eligibility criteria. These findings indicate that when performing RFA on needle biopsy-diagnosed DCIS, the risk of underdiagnosed invasive cancer must be considered.

In this study, lesion size was identified as a significant factor for underdiagnosis, both as a categorical and continuous variable. Consistently, lesion size was identified as a predictor of underdiagnosis in biopsy-diagnosed DCIS [12], with a larger lesion size correlating with higher risk for underdiagnosis [30]. Palpability was reported as a predictor of underdiagnosis. Consistently, this study observed a tendency for correlation between palpability and underdiagnosis. By contrast, mass formation, type of needle biopsy, and HR and HER2 statuses were not recognized as predictors of underdiagnosis in this study. Although mass lesions identified on mammography are risk factors for underdiagnosis [12], advances in preoperative imaging tests, such as breast ultrasound and contrast-enhanced MRI, facilitated tumor identification, potentially resulting in this result. Although the type of needle biopsy was a predictor of underdiagnosis [34], the choice of needle biopsy in this study was at the physician's discretion, indicating that the influence of selection bias cannot be ruled out. HR and HER2 were reported as predictors for underdiagnosis [29]. However, why HR and HER2 were not recognized as predictors in this trial remain unclear, but differences in patient backgrounds may have influenced the results.

The inappropriate omission of adjuvant systemic therapy due to underdiagnosis of invasive disease is a major concern when administering RFA in needle biopsy-diagnosed DCIS. Adjuvant systemic therapy is generally considered for invasive breast cancer in surgical specimens, including adjuvant chemotherapy for pT1b or higher HR-negative disease [13]. In a study using the National Cancer Database for needle biopsy-diagnosed DCIS, the frequency of underdiagnosis was 22.2% among women clinically diagnosed with non-high grade DCIS [30]. The study showed that ≥ pT1b was observed in 39.1% among the underdiagnosed cases, with endocrine therapy administered to 54% and chemotherapy to 16.5% of the cases. In this study, ≥T1b was observed in 15 (37.5%) among the underdiagnosed lesions, with adjuvant endocrine therapy and chemotherapy administered to 26 (65.0%) and 6 (15.0%) of the lesions, respectively. These findings suggest that a proportion of cases with needle biopsy-diagnosed DCIS eligible for RFA require adjuvant systemic therapy, highlighting the risk of poorer prognosis due to inadequate systemic therapy. However, HR-positive, HER2-negative pT1a/bN0M0 breast cancer has a favorable prognosis, regardless of endocrine therapy administration [35]. In HR-positive, HER2-negative needle biopsy DCIS, the impact of undertreatment due to underdiagnosis may be minimal. Therefore, the risk of underdiagnosis should be carefully considered when determining RFA eligibility for needle biopsy-diagnosed HR-negative DCIS.

This study has some limitations. Because this study design is retrospective and cohort size is relatively small, selection bias cannot be excluded. The different results of HR and HER2 for prediction of underdiagnosis between this study and others should be evaluated in further study. To address these issues, a multicenter prospective study must evaluate the incidence and predictors of underdiagnosis, and a diagnostic prediction model should be developed for underdiagnosis in patients with needle biopsy-diagnosed DCIS.

This study showed that a certain proportion of lesions underdiagnosed for invasive cancer may require adjuvant systemic therapy, including chemotherapy, in needle biopsy-diagnosed DCIS eligible for RFA. When performing RFA in needle biopsy-diagnosed DCIS, it is important to consider the potential for underdiagnosis and the subsequent need for adjuvant systemic therapy.

DCIS Ductal carcinoma in situ

ER Estrogen receptor

PgR Progesterone receptor

HER2 Human epidermal growth factor 2

HR Hormone Receptor

RFA Radiofrequency ablation

Ethics approval and consent to participate

Consent for publication

Not applicable.

Availability of data and materials

The datasets used during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors report no competing of interest concerning the materials or methods used in this manuscript or findings specified in this paper.

Funding

This study was conducted with the support of the National University Corporation Operating Grant.

Author contributions

H.S., S.S. and M.O. contributed to the conception and design. H.S., M.F., K.S., H.I., A.A., E.H., and A.K. contributed to the curation, analysis, and interpretation of data. H.S., M.F., and S.S. contributed to the formal analysis. H.S., S.S., and M.O. contributed to drafting and revision of the article. H.S. and M.O. contributed to funding acquisition. All authors read and approved the final manuscript.

Acknowledgments

The authors thank Ulatus (https://www.ulatus.jp) for their assistance with manuscript translation and editing.

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No competing interests reported.

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Evaluating the risk of underdiagnosis of invasive breast cancer in needle biopsy-diagnosed ductal carcinoma in situ eligible for radiofrequency ablation

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Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study design

Clinicopathological factors

Statistical analysis

Results

Patient characteristics

Frequency of underdiagnosis

Predictors of underdiagnosis

pT stage distribution and adjuvant systemic therapy in underdiagnosed lesions

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1