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Comment
. 2022 Jan 15;28(2):308-317.
doi: 10.1158/1078-0432.CCR-21-2260. Epub 2021 Oct 19.

Neoadjuvant Chemotherapy and Immunotherapy in Luminal B-like Breast Cancer: Results of the Phase II GIADA Trial

Maria Vittoria Dieci #  1   2 , Valentina Guarneri #  3   2 , Anna Tosi  3 , Giancarlo Bisagni  4 , Antonino Musolino  5   6 , Simon Spazzapan  7 , Gabriella Moretti  4 , Grazia Maria Vernaci  3   2 , Gaia Griguolo  3   2 , Tommaso Giarratano  2 , Loredana Urso  3 , Francesca Schiavi  8 , Claudia Pinato  8 , Giovanna Magni  9 , Marcello Lo Mele  10 , Gian Luca De Salvo  9 , Antonio Rosato #  3   11 , Pierfranco Conte #  3   2
Affiliations
Comment

Neoadjuvant Chemotherapy and Immunotherapy in Luminal B-like Breast Cancer: Results of the Phase II GIADA Trial

Maria Vittoria Dieci et al. Clin Cancer Res. .

Abstract

Purpose: The role of immunotherapy in hormone receptor (HR)-positive, HER2-negative breast cancer is underexplored.

Patients and methods: The neoadjuvant phase II GIADA trial (NCT04659551, EUDRACT 2016-004665-10) enrolled stage II-IIIA premenopausal patients with Luminal B (LumB)-like breast cancer (HR-positive/HER2-negative, Ki67 ≥ 20%, and/or histologic grade 3). Patients received: three 21-day cycles of epirubicin/cyclophosphamide followed by eight 14-day cycles of nivolumab, triptorelin started concomitantly to chemotherapy, and exemestane started concomitantly to nivolumab. Primary endpoint was pathologic complete response (pCR; ypT0/is, ypN0).

Results: A pCR was achieved by 7/43 patients [16.3%; 95% confidence interval (CI), 7.4-34.9]; the rate of residual cancer burden class 0-I was 25.6%. pCR rate was significantly higher for patients with PAM50 Basal breast cancer (4/8, 50%) as compared with other subtypes (LumA 9.1%; LumB 8.3%; P = 0.017). Tumor-infiltrating lymphocytes (TIL), immune-related gene-expression signatures, and specific immune cell subpopulations by multiplex immunofluorescence were significantly associated with pCR. A combined score of Basal subtype and TILs had an AUC of 0.95 (95% CI, 0.89-1.00) for pCR prediction. According to multiplex immunofluorescence, a switch to a more immune-activated tumor microenvironment occurred following exposure to anthracyclines. Most common grade ≥3 treatment-related adverse events (AE) during nivolumab were γ-glutamyltransferase (16.7%), alanine aminotransferase (16.7%), and aspartate aminotransferase (9.5%) increase. Most common immune-related AEs were endocrinopathies (all grades 1-2; including adrenal insufficiency, n = 1).

Conclusions: Luminal B-like breast cancers with a Basal molecular subtype and/or a state of immune activation may respond to sequential anthracyclines and anti-PD-1. Our data generate hypotheses that, if validated, could guide immunotherapy development in this context.

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Figures

Figure 1. CONSORT diagram.
Figure 1.
CONSORT diagram.
Figure 2. Association of gene-expression parameters and TILs with pCR. A, Rate of pCR within different molecular intrinsic subtypes. B, Volcano plot showing differential expression of baseline gene-expression signatures assessed with the NanoString Breast Cancer 360 Panel in tumors achieving pCR as compared with tumors not achieving pCR. Displayed is the log2 fold difference in each gene-expression signature score between pCR and non-pCR. The gray dashed lines indicate the thresholds for unadjusted statistical significance (P < 0.05 and P < 0.01). Every dot represents one gene-expression signature. Blue dots represent gene signatures showing an association with pCR at the level of adjusted P < 0.05. C, Boxplot showing TIL levels in pCR vs. non-pCR patients. D, ROC showing the performance of the combined Basal subtype and TILs to predict pCR.
Figure 2.
Association of gene-expression parameters and TILs with pCR. A, Rate of pCR within different molecular intrinsic subtypes. B, Volcano plot showing differential expression of baseline gene-expression signatures assessed with the NanoString Breast Cancer 360 Panel in tumors achieving pCR as compared with tumors not achieving pCR. Displayed is the log2 fold difference in each gene-expression signature score between pCR and non-pCR. The gray dashed lines indicate the thresholds for unadjusted statistical significance (P < 0.05 and P < 0.01). Every dot represents one gene-expression signature. Blue dots represent gene signatures showing an association with pCR at the level of adjusted P < 0.05. C, Boxplot showing TIL levels in pCR vs. non-pCR patients. D, ROC showing the performance of the combined Basal subtype and TILs to predict pCR.
Figure 3. A, Boxplots showing intratumoral immune cell populations by mIHC with significant different levels in pCR vs. non-pCR patients at t0. B, Representative pictures of mIHC staining at t0 in pCR and non pCR patients; original magnification 20×. C, Significant changes in TILs and intratumoral immune cell populations by mIHC from t0 to t1 in matched paired samples, with * indicating outlier values, red lines for patients with pCR, yellow lines for patients with RCB I, and gray lines for other patients. D, Representative pictures of a lymphoid mIHC panel at t0 and t1 from the same patient; original magnification 20×. Color code for mIHC pictures of checkpoint panel: CD3 in magenta, PD-1 in yellow, CD68 in white, CD163 in green, PD-L1 in red, pan-cytokeratin in cyan, nuclei in blue. Color code for mIHC pictures of lymphoid panel: CD8 in magenta, CD4 in yellow, granzyme B in green, FoxP3 in white, CD20 in orange, pan-cytokeratin in cyan, nuclei in blue.
Figure 3.
A, Boxplots showing intratumoral immune cell populations by mIHC with significant different levels in pCR vs. non-pCR patients at t0. B, Representative pictures of mIHC staining at t0 in pCR and non pCR patients; original magnification 20×. C, Significant changes in TILs and intratumoral immune cell populations by mIHC from t0 to t1 in matched paired samples, with * indicating outlier values, red lines for patients with pCR, yellow lines for patients with RCB I, and gray lines for other patients. D, Representative pictures of a lymphoid mIHC panel at t0 and t1 from the same patient; original magnification 20×. Color code for mIHC pictures of checkpoint panel: CD3 in magenta, PD-1 in yellow, CD68 in white, CD163 in green, PD-L1 in red, pan-cytokeratin in cyan, nuclei in blue. Color code for mIHC pictures of lymphoid panel: CD8 in magenta, CD4 in yellow, granzyme B in green, FoxP3 in white, CD20 in orange, pan-cytokeratin in cyan, nuclei in blue.
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  • Selected Articles from This Issue.
    [No authors listed] [No authors listed] Clin Cancer Res. 2022 Jan 15;28(2):247. doi: 10.1158/1078-0432.CCR-28-2-HI. Clin Cancer Res. 2022. PMID: 35045957 No abstract available.

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