TY - JOUR
T1 - Prognostic and predictive value of HER2 expression in ductal carcinoma in situ
T2 - Results from the UK/ANZ DCIS randomized trial
AU - Thorat, Mangesh A.
AU - Levey, Pauline M.
AU - Louise Jones, J.
AU - Pinder, Sarah E.
AU - Bundred, Nigel J.
AU - Fentiman, Ian S.
AU - Cuzick, Jack
N1 - Funding Information:
This work was funded by Cancer Research UK grants C569/A12061 (to J. Cuzick, M.A. Thorat) and C569/A16891 (to J. Cuzick, M.A. Thorat). Ventana Medical Systems, Inc. Tucson, AZ provided INFORM HER2 Dual ISH DNA Probe Cocktail Assay kits and reagents without charge.
Funding Information:
M.A. Thorat reports grants from Cancer Research UK and Breast Cancer Research Foundation, as well as non-financial support from Ventana Medical Systems, Inc. Tucson, AZ during the conduct of the study. S.E. Pinder reports personal fees from Roche, AstraZeneca, and Exact Science outside the submitted work. J. Cuzick reports grants from Cancer Research UK and Breast Cancer Research Foundation. No disclosures were reported by the other authors.
Publisher Copyright:
2021 The Authors; Published by the American Association for Cancer Research
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Purpose: HER2 is overexpressed more frequently in ductal carcinoma in situ (DCIS) than in invasive breast cancer but its prognostic significance and predictive role for radiotherapy has not been clearly established. We investigated the prognostic and predictive value of HER2 overexpression in DCIS. Experimental Design: HER2 expression was evaluated by IHC using the HercepTest in samples from UK/ANZ DCIS trial participants (n ¼ 755) with IHC 3þ expression categorized as HER2 positive for primary analyses. Sensitivity analyses included HER2 categorization as negative (IHC 0,1þ), equivocal (IHC 2þ), and positive (IHC 3þ) and analyses restricted to a nested case–control component where 181 cases (with recurrence) were matched to 362 controls by treatment arm and age. Results: Two-hundred and forty-five (34.4%) of evaluable 713 samples [181 ipsilateral breast events (IBE)] were HER2 positive. HER2 overexpression was associated with significantly increased risk of IBE [HR ¼ 2.29; 95% confidence interval (95% CI), 1.64–3.14; P < 0.0001] and in situ IBE (DCIS-IBE; HR ¼ 2.90; 95% CI, 1.91–4.40; P < 0.0001), but not of invasive IBE (I-IBE; HR ¼ 1.40; 95% CI, 0.81–2.42; P ¼ 0.23; Pheterogeneity ¼ 0.04). Inclusion of HER2 significantly improved [Dx2 (1d.f.) 12.25; P ¼ 0.0005] a prognostic model of clinicopathological and treatment variables, HER2 being an independent predictor of IBE (multivariate HR ¼ 1.91; 95% CI, 1.33–2.76; P ¼ 0.0004). Radiotherapy benefit in preventing DCIS-IBE was significantly greater (Pheterogeneity ¼ 0.04) in HER2-positive DCIS (HR ¼ 0.16; 95% CI, 0.07–0.41) compared with HER2-negative DCIS (HR ¼ 0.58; 95% CI, 0.28–1.19). Conclusions: HER2 overexpression is associated with significantly increased risk of in situ recurrence and is also predictive of radiotherapy benefit, with greater reductions in in situ but not invasive recurrences in HER2-positive DCIS.
AB - Purpose: HER2 is overexpressed more frequently in ductal carcinoma in situ (DCIS) than in invasive breast cancer but its prognostic significance and predictive role for radiotherapy has not been clearly established. We investigated the prognostic and predictive value of HER2 overexpression in DCIS. Experimental Design: HER2 expression was evaluated by IHC using the HercepTest in samples from UK/ANZ DCIS trial participants (n ¼ 755) with IHC 3þ expression categorized as HER2 positive for primary analyses. Sensitivity analyses included HER2 categorization as negative (IHC 0,1þ), equivocal (IHC 2þ), and positive (IHC 3þ) and analyses restricted to a nested case–control component where 181 cases (with recurrence) were matched to 362 controls by treatment arm and age. Results: Two-hundred and forty-five (34.4%) of evaluable 713 samples [181 ipsilateral breast events (IBE)] were HER2 positive. HER2 overexpression was associated with significantly increased risk of IBE [HR ¼ 2.29; 95% confidence interval (95% CI), 1.64–3.14; P < 0.0001] and in situ IBE (DCIS-IBE; HR ¼ 2.90; 95% CI, 1.91–4.40; P < 0.0001), but not of invasive IBE (I-IBE; HR ¼ 1.40; 95% CI, 0.81–2.42; P ¼ 0.23; Pheterogeneity ¼ 0.04). Inclusion of HER2 significantly improved [Dx2 (1d.f.) 12.25; P ¼ 0.0005] a prognostic model of clinicopathological and treatment variables, HER2 being an independent predictor of IBE (multivariate HR ¼ 1.91; 95% CI, 1.33–2.76; P ¼ 0.0004). Radiotherapy benefit in preventing DCIS-IBE was significantly greater (Pheterogeneity ¼ 0.04) in HER2-positive DCIS (HR ¼ 0.16; 95% CI, 0.07–0.41) compared with HER2-negative DCIS (HR ¼ 0.58; 95% CI, 0.28–1.19). Conclusions: HER2 overexpression is associated with significantly increased risk of in situ recurrence and is also predictive of radiotherapy benefit, with greater reductions in in situ but not invasive recurrences in HER2-positive DCIS.
UR - http://www.scopus.com/inward/record.url?scp=85117786361&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-1239
DO - 10.1158/1078-0432.CCR-21-1239
M3 - Article
C2 - 34380636
AN - SCOPUS:85117786361
SN - 1078-0432
VL - 27
SP - 5317
EP - 5324
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -
