Independent prognostic ımpact of perineural ınvasion in breast cancer patients with residual disease after neoadjuvant chemotherapy

Elçiçek, Ömer Faruk; Yalıcı, Özge; Çavdar, Eyyüp; Gedik, Ezel; Öznur, Meltem; Avcı, Okan; Şeber, Erdoğan Selçuk

doi:10.1590/1806-9282.20252145

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Sumário

ORIGINAL ARTICLE • Rev. Assoc. Med. Bras. 72 (5) • 2026 • https://doi.org/10.1590/1806-9282.20252145 linkcopy

Independent prognostic ımpact of perineural ınvasion in breast cancer patients with residual disease after neoadjuvant chemotherapy

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVE: Perineural invasion is a well-established adverse prognostic factor in several malignancies, yet its prognostic role in breast cancer remains controversial.

METHODS: We retrospectively analyzed 400 breast cancer patients treated with neoadjuvant chemotherapy between 2012 and 2025 who had residual disease (non-pCR) at surgery. Clinicopathological variables, recurrence-free survival, and overall survival were evaluated using Cox proportional hazards models.

RESULTS: Perineural invasion was identified in 42.5% of the cohort and associated with larger tumor burden, lymphovascular invasion, and nodal metastasis (p<0.01). Perineural invasion-positive status correlated with significantly inferior median recurrence-free survival (100.5 vs. 120.4 months; HR 1.77, p=0.008) and overall survival (108.5 vs. 133.6 months; HR 3.11, p<0.001). Multivariate analysis confirmed perineural invasion as a robust independent predictor of shorter recurrence-free survival and overall survival. The adverse impact was evident across all molecular subtypes, particularly HR+/HER2- and HER2+ groups.

CONCLUSION: Perineural invasion is a strong independent prognostic factor for recurrence-free survival and overall survival in breast cancer patients with residual disease after neoadjuvant chemotherapy. Reporting perineural invasion status in routine pathology evaluations may aid in risk stratification for this high-risk population.

KEYWORDS:
Breast neoplasms; Neoplasm invasiveness; Prognosis; Neoadjuvant therapy; Survival analysis

Clinicopathological characteristics	n (%)	PNI positive n (%)	p-value
Age
<40 (young adult)	71 (17.8)	26 (36.6)	0.269
≥40	329 (82.2)	144 (43.8)	0.269
Menopausal status
Premenopausal	208 (48.0)	83 (39.9)	0.274
Peri-postmenopausal	192 (52.0)	87 (45.3)	0.274
Histologic type
Ductal	318 (79.5)	131 (41.2)	0.298
Others	82 (20.5)	39 (47.6)	0.298
PgR status
Negative	112 (28.0)	42 (37.5)	0.207
Positive	288 (72.0)	128 (44.4)	0.207
ER status
Negative	78 (19.5)	33 (42.3)	0.969
Positive	322 (80.5)	137 (42.5)	0.969
Her2 status
Negative	298 (74.5)	132 (44.3)	0.214
Positive	102 (25.5)	38 (31.4)	0.214
Ki-67
<18	109 (27.2)	49 (44.6)	0.543
≥18	291 (72.8)	121 (41.6)	0.543
Histologic grade
Grade 1–2	267 (66.8)	112 (41.9)	0.751
Grade 3	133 (33.2)	58 (43.6)	0.751
T size
≤2 cm	131 (32.8)	41 (31.3)	0.002 s
>2 cm	269 (67.2)	129 (47.8)	0.002 s
LVI status
Negative	238 (59.5)	39 (16.4)	<0.001 s
Positive	162 (40.5)	131 (80.1)	<0.001 s
Axillary status
Negative	125 (31.2)	18 (14.4)	<0.001 s
Positive	275 (68.8)	152 (55.3)	<0.001 s

Variable	Univariate RFS HR (95%CI)	p	Univariate OS HR (95%CI)	p	Multivariate RFS HR (95%CI)	p	Multivariate OS HR (95%CI)	p
Age (<40/≥40)	0.80 (0.50–1.29)	0.360	0.90 (0.50–1.65)	0.732	–	–	–	–
Menopause status (pre/peri–post)	1.26 (0.85–1.86)	0.247	1.00 (0.62–1.62)	0.997	–	–	–	–
Histologic type (ductal/others)	0.93 (0.58–1.50)	0.761	1.27 (0.73–2.21)	0.394	–	–	–	–
PgR status (negative/positive)	0.62 (0.42–0.93)	0.019	0.53 (0.33–0.87)	0.011	0.65 (0.32–1.32)	0.235	0.87 (0.31–2.45)	0.793
ER status (negative/positive)	0.55 (0.39–0.84)	0.005	0.39 (0.23–0.64)	<0.001	0.88 (0.41–1.88)	0.742	0.49 (0.29–0.84)	0.009
Ki67 (<18/≥18)	1.65 (1.03–2.65)	0.039	2.45 (1.27–4.73)	0.007	1.36 (0.83–2.23)	0.224	1.91 (0.97–3.78)	0.062
HER2 status (negative/positive)	1.10 (0.71–1.70)	0.667	1.13 (0.66–1.95)	0.655	–	–	–	–
Grade (≤2/3)	2.13 (1.44–3.14)	<0.001	2.96 (1.80–4.85)	<0.001	1.89 (1.24–2.88)	0.003	2.25 (1.32–3.82)	0.003
cT size (≤2 cm/>2 cm)	1.23 (0.81–1.87)	0.338	1.53 (0.88–2.65)	0.134	–	–	–	–
LVI (negative/positive)	2.14 (1.45–3.16)	<0.001	1.82 (1.12–2.97)	0.016	Excluded*	–	Excluded*	–
PNI (negative/positive)	2.24 (1.51–3.30)	<0.001	3.05 (1.83–5.07)	<0.001	1.78 (1.17–2.70)	0.007	2.60 (1.49–4.54)	<0.001
Axillary status (negative/positive)	2.36 (1.45–3.85)	<0.001	2.16 (1.20–3.91)	0.011	2.33 (1.37–3.98)	0.002	1.87 (0.97–3.62)	0.062

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[T1FN1] ^sSignificant values are indicated in bold. Her2: human epidermal growth factor receptor 2; ER: estrogen receptor; PgR: progesterone receptor; LVI: Lymphovascular invasion; PNI: perineural invasion.