Can neoadjuvant chemotherapy be replaced with immune checkpoint blockade combined with dual anti-HER2 antibodies for HER2-enriched breast cancer?

The West German Study Group (WSG) has recently reported the results of a relatively small but provocative phase 2 trial (WSG-KEYRICHED-1) testing the hypothesis that de-escalation of neoadjuvant therapy for HER2⁺ breast cancers, omitting neoadjuvant chemotherapy (NCT) entirely and substituting immune checkpoint blockade (ICB), could increase the pathologic complete response (pCR) rates compared to the historical rate with HER2-targeted therapy alone (1). They used the “target” pCR rate of 40% to improve upon, based on past experiences with chemotherapy-free regimens, as reported from trials such as NeoALTTO and NeoSphere (2,3). In NeoALTTO, for example, a total pCR (no invasive cancer in the breast or regional nodes, i.e., ypT0/Tis N0) rate of 46.8% was achieved with the combination of trastuzumab and lapatinib. In the NeoSphere trial, however, the total pCR rate (breast & nodes) was only 11.2% (16.8% in breast) with dual anti-HER2 antibodies, vs. 39% with the addition of a taxane (3). Of note, relative to comments below, roughly half of the tumors in those two studies were estrogen receptor-positive (ER⁺) and/or progesterone receptor-positive (PR⁺).

Neoadjuvant trials with chemotherapy plus dual antibodies have reported pCR rates in excess of 50–70%, a high bar indeed (4-9). Addition of ICB to chemotherapy + HER2-targeting, however, has not proven to add benefit in the setting of neoadjuvant treatment for HER2⁺ breast cancer (10,11). These studies used atezolizumab to block PD-L1 rather than the anti-PD-1 antibody pembrolizumab, which was used in this study. The KATE2 trial testing addition of atezolizumab to trastuzumab-emtansine for advanced HER2⁺ breast cancer also did not show any improvement compared to trastuzumab-emtansine alone (12). The recently reported Neo-HIP trial compared paclitaxel (T) + trastuzumab (H) + pertuzumab (P) vs. THP + pembrolizumab (THP-K) vs. TH-K in the neoadjuvant setting (13). Adding pembrolizumab to THP increased the total pCR rate from 51.9% to 67.2%. The arm without pertuzumab was discontinued because of a low pCR rate (<40%). While this study showed the potential benefit of adding ICB in the neoadjuvant setting for HER2⁺ breast cancer, all three arms included paclitaxel chemotherapy. A recent randomized trial in the setting of metastatic HER2⁺ breast cancer testing the addition of atezolizumab to chemotherapy + dual anti-HER2 therapy, NRG BR004 (NCT03199885), was halted early because of excess deaths in the experimental arm.

The addition of ICB to anti-HER2 antibody treatment was certainly a logical step to consider, given that HER2⁺ tumors tend to have high tumor mutational burdens (TMBs) and high levels of tumor-infiltrating lymphocytes (TILs) (14-16). Moreover, the immune profile of HER2⁺ breast cancers, based on TIL, immune signatures and PD-L1 expression has been found to be predictive of response to neoadjuvant therapy (17-20). In addition to inhibition of HER2 signaling, pre-clinical and clinical evidence suggest that activation of immune mechanisms is also involved in the efficacy of HER2-targeting antibodies (2,21-27).

Despite the lack of statistically significant improvement in the pCR rate (47% of the 43 subjects with centrally confirmed pathologic responses, compared to the “benchmark” of 40%), the translational biomarker studies suggest potential subsets of patients who might be appropriate for a larger phase 3 study comparing this approach to the more standard neoadjuvant approach of chemotherapy plus dual anti-HER2 blockade.

For example, tumors that were scored as PD-L1⁺ [combined positive score (CPS) ≥1] were associated with pCR of 58% compared to only 22% for PD-L1 negative tumors. This is similar to the experience of ICB benefit observed for metastatic triple-negative breast cancers (TNBCs) (28,29), but differs from the Keynote-522 neoadjuvant trial (30,31). In Keynote-522, ICB was beneficial regardless of PD-L1 status, although higher PD-L1 scores were associated with better outcomes in both arms of the study. Other biomarkers that were associated with a higher likelihood of pCR in the WSG study included higher grade and higher expression of ERBB2, PD-1 and PD-L1 mRNAs. Conversely, detectable plasma circulating tumor DNA (ctDNA) was associated with a lower likelihood of pCR with this chemotherapy-free regimen. It should be noted that in the discussion, the authors stated that “translational research suggests that higher baseline expressions of ERBB2, PD-1, and PD-L1, and ctDNA are negatively associated with pathological complete response after neoadjuvant pembrolizumab plus dual HER2 blockade.” Aside from plasma ctDNA, this contradicts the data presented, and I have confirmed by communication with the authors that this comment was an error. There was no significant impact of TIL or TMB on the rate of pCR in this study, but this could be a result of the small sample size involved.

The lower pCR rate for PR⁺ tumors (21% vs. 59% for PR⁻) is not surprising, given that hormone receptor (HR)⁺HER2⁺ tumors have also been found to be less likely to achieve pCR with chemotherapy + HER2-targeted therapy or dual HER2-targeted therapy alone in multiple studies, including in the neoadjuvant setting (2,3,32-40). As reviewed by Schedin et al., so-called “triple positive” breast cancers are particularly resistant to HER2-targeted therapies, even with the addition of chemotherapy (32). Although the differences in pCR for ER⁺ vs. ER⁻ tumors in the WSG study was in the same direction as for PR status (59% vs. 38%), this did not reach the same level of significance as for PR; this is likely a result of the small sample size, particularly for ER⁻PR⁺ tumors (which is difficult to decipher from Tab. 2). As described in the Schedin et al.’s review, roughly half of HER2⁺ cancers are also HR⁺, but only a small minority (<10%) of HER2⁺ tumors are likely to be ER⁻PR⁺ (32). Moreover, less than half of HR⁺/HER2⁺ breast cancers belong to the HER2-enriched subtype, with the remaining being luminal A or B. In any future trials of chemotherapy-free neoadjuvant treatments testing HER2-targeting + ICB, as proposed by the authors, it would be reasonable to exclude patients with any HR⁺ tumors, i.e., ER⁺ and/or PR⁺. Given that HER2⁺HR⁺ breast cancers have somewhat lower levels of TIL than HR⁻HER2⁺ tumors (1,17,41), addition of ICB is less likely to be valuable for these so-called “triple positive” cancers without other treatments to modify the tumor microenvironment (TME). Currently, based on the cross-talk of HR and HER2 signaling and the CDK4/6 pathway, neoadjuvant trials of chemotherapy-free treatment with HER2-targeted therapy + endocrine therapy + CDK4/6 inhibitors would be a reasonable approach, which has been explored in a phase 2 trial and is being considered for future trials (32,42).

Tumors that were scored 3+ for HER2 expression were also more likely to experience pCR (20/39 or 51%) than the small number of tumors that were scored 2+ (0/4). It may have been that pre-selecting tumors for this trial determined to be of the HER2 enriched subtype by the PAM50 RNA expression assay resulted in only a few patients being included with 2+ HER2 immunohistochemistry (IHC) scores. For the design of a subsequent larger trial to assess the clinical effectiveness of dual HER2 blockade + ICB vs. HER2 blockade + chemotherapy, some of these biomarkers, including the PAM50 score, might not be as practical for patient selection as simply limiting entry to patients whose tumors are 3+ for HER2 by IHC, HR-negative and with a PD-L1 CPS score ≥1. It might be reasonable based on this study to exclude patients with positive ctDNA, but it might be more valuable and more interesting to include those patients and, as was done here, follow ctDNA serially to determine whether it is predictive of pCR as well as long-term outcomes with either chemotherapy-free treatment or with HER2 blockade + chemotherapy. Indeed, a similar strategy is being implemented in a current U.S. trial (EA1211) but instead evaluating serial positron emission tomography (PET) scans during neoadjuvant therapy of HER2⁺ breast cancers. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-64 also involves collecting blood for ctDNA assessment during and after NCT for TNBC and HER2⁺ breast cancers.

One question about the relevance of this trial for HER2⁺ breast cancers overall was that 51% of the subjects were classified by the authors as having stage I cancers, although 58% had T2 tumors, which would make them stage II, according to American Joint Commission on Cancer (AJCC) 8^th edition criteria (43). One might have assumed that these patients would have had higher pCR rates than those with higher stages, but in fact this was not the case. It would be important to know whether the pre-treatment staging of these patients included axillary ultrasound, which is now commonly practiced in U.S. centers for newly diagnosed invasive breast cancers.

As pointed out by the authors in the introduction, multiple studies of neoadjuvant therapy for breast cancer, including HER2⁺ cancers treated with chemotherapy + HER2-targeted therapies, have noted an association between pCR and improved long-term outcomes such as event-free survival (EFS) and overall survival (OS) (44-46). However, as has also been discussed repeatedly, one treatment that increases the rate of pCR compared to another does not necessarily guarantee that it will lead to increased disease-free survival (DFS) or OS (44,47). In fact, a metanalysis of eleven neoadjuvant trials specifically for HER2⁺ breast cancers, using individual patient data, found that despite clear patient level associations between pCR and EFS and OS, trial-level associations were weak (11). The conclusion of this study was that, despite the usefulness of pCR for clinical patient management for HER2⁺ breast cancers, it could not be used as a surrogate for long-term outcomes.

Final thoughts: we should be mindful of how low a rate of pCR we are willing to “settle” for by de-escalating neoadjuvant treatment, as this could jeopardize recent and ongoing efforts to de-escalate post-neoadjuvant therapies. These include less surgery, omitting radiation and less aggressive adjuvant systemic therapy. For example, it was shown long ago that NCT can increase the likelihood of breast conservation surgery (48,49), but more recent studies have explored the possibility of omitting breast surgery altogether in patients whose breast tumors have regressed to the point that pCR is highly likely, based on imaging and biopsies (50). It has already become common practice to omit axillary lymph node dissection in patients whose initially positive nodes have undergone pCR, based on sentinel node biopsy/targeted axillary dissection (51-56). Based on the recently reported NSABP B-51 trial, it is likely that many patients with clinically positive nodes may no longer need to receive regional nodal irradiation if axillary nodes are negative after NCT (57). Specifically for HER2⁺ tumors, a small study followed patients with pCR and breast conserving surgery without radiation and documented no local recurrences (58). A larger prospective randomized NRG trial (NRG-BR008, NCT05705401) was intended to determine whether breast irradiation could be omitted after breast-conserving surgery in patients with low-risk HER2⁺ breast cancers, including those who experienced pCR with neoadjuvant therapy; unfortunately, this trial was recently halted because of low accrual. The ongoing EA1181 trial (NCT04266249) will determine whether de-escalation of adjuvant systemic therapy for patients who experience pCR with THP neoadjuvant treatment is safe. A trial recently activated by the Alliance group (A12303, NCT06876714) for HER2⁺ breast cancers after a pCR is also intended to determine whether systemic therapy can be de-escalated, shortening the duration of HP from a total of 12 to 6 months. Finally, it should be noted that some of the possible side effects of ICB, such as hypothyroidism and adrenal insufficiency can be life-long, which may be more concerning than the toxicities of chemotherapy, particularly with regimens that are anthracycline-free.

In summary, this interesting report suggests a possible subset of patients who might avoid chemotherapy altogether by substituting ICB added to effective HER2-targeted therapies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Breast Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-57/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-57/coif). H.D.B. reports institutional support for a clinical trial from Merck; serves on a Breast Cancer Advisory Board for Merck; and holds stock in Abbvie. The author has no other conflicts of interest to declare.

Ethical Statement:The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kuemmel S, Graeser M, Schmid P, et al. Chemotherapy-free neoadjuvant pembrolizumab combined with trastuzumab and pertuzumab in HER2-enriched early breast cancer (WSG-KEYRICHED-1): a single-arm, phase 2 trial. Lancet Oncol 2025;26:629-40. [Crossref] [PubMed]
2. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633-40. [Crossref] [PubMed]
3. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:25-32. [Crossref] [PubMed]
4. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol 2013;14:1183-92. [Crossref] [PubMed]
5. Swain SM, Ewer MS, Viale G, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 2018;29:646-53. [Crossref] [PubMed]
6. Nitz UA, Gluz O, Christgen M, et al. De-escalation strategies in HER2-positive early breast cancer (EBC): final analysis of the WSG-ADAPT HER2+/HR- phase II trial: efficacy, safety, and predictive markers for 12 weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel. Ann Oncol 2017;28:2768-72. [Crossref] [PubMed]
7. Carey LA, Berry DA, Cirrincione CT, et al. Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. J Clin Oncol 2016;34:542-9. [Crossref] [PubMed]
8. Clark AS, Yau C, Wolf DM, et al. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2(+) breast cancer in the adaptively randomized I-SPY2 trial. Nat Commun 2021;12:6428. [Crossref] [PubMed]
9. van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018;19:1630-40. [Crossref] [PubMed]
10. Huober J, Barrios CH, Niikura N, et al. Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. J Clin Oncol 2022;40:2946-56. [Crossref] [PubMed]
11. Squifflet P, Saad ED, Loibl S, et al. Re-Evaluation of Pathologic Complete Response as a Surrogate for Event-Free and Overall Survival in Human Epidermal Growth Factor Receptor 2-Positive, Early Breast Cancer Treated With Neoadjuvant Therapy Including Anti-Human Epidermal Growth Factor Receptor 2 Therapy. J Clin Oncol 2023;41:2988-97. [Crossref] [PubMed]
12. Emens LA, Esteva FJ, Beresford M, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol 2020;21:1283-95. [Crossref] [PubMed]
13. McArthur H, Chan I, Leal J, et al. Abstract RF3-05: A Phase 2 Study of Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP). Clin Cancer Res 2025;31:RF3-05.
14. Thomas A, Routh ED, Pullikuth A, et al. Tumor mutational burden is a determinant of immune-mediated survival in breast cancer. Oncoimmunology 2018;7:e1490854. [Crossref] [PubMed]
15. Nuciforo P, Pascual T, Cortés J, et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade. Ann Oncol 2018;29:170-7. [Crossref] [PubMed]
16. Dieci MV, Prat A, Tagliafico E, et al. Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial. Ann Oncol 2016;27:1867-73. [Crossref] [PubMed]
17. Salgado R, Denkert C, Campbell C, et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol 2015;1:448-54. [Crossref] [PubMed]
18. Gao ZH, Li CX, Liu M, et al. Predictive and prognostic role of tumour-infiltrating lymphocytes in breast cancer patients with different molecular subtypes: a meta-analysis. BMC Cancer 2020;20:1150. [Crossref] [PubMed]
19. Hou Y, Nitta H, Wei L, et al. PD-L1 expression and CD8-positive T cells are associated with favorable survival in HER2-positive invasive breast cancer. Breast J 2018;24:911-9. [Crossref] [PubMed]
20. Wimberly H, Brown JR, Schalper K, et al. PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. Cancer Immunol Res 2015;3:326-32. [Crossref] [PubMed]
21. Barok M, Isola J, Pályi-Krekk Z, et al. Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance. Mol Cancer Ther 2007;6:2065-72. [Crossref] [PubMed]
22. Kute TE, Savage L, Stehle JR Jr, et al. Breast tumor cells isolated from in vitro resistance to trastuzumab remain sensitive to trastuzumab anti-tumor effects in vivo and to ADCC killing. Cancer Immunol Immunother 2009;58:1887-96. [Crossref] [PubMed]
23. Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 2004;10:5650-5. [Crossref] [PubMed]
24. Lee SC, Srivastava RM, López-Albaitero A, et al. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res 2011;50:248-54. [Crossref] [PubMed]
25. Stagg J, Loi S, Divisekera U, et al. Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proc Natl Acad Sci U S A 2011;108:7142-7. [Crossref] [PubMed]
26. Musolino A, Naldi N, Dieci MV, et al. Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer. Pharmacogenomics J 2016;16:472-7. [Crossref] [PubMed]
27. Bianchini G, Gianni L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol 2014;15:e58-68. [Crossref] [PubMed]
28. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396:1817-28. [Crossref] [PubMed]
29. Emens LA, Adams S, Barrios CH, et al. First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. Ann Oncol 2021;32:983-93. [Crossref] [PubMed]
30. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 2020;382:810-21. [Crossref] [PubMed]
31. Schmid P, Cortes J, Dent R, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med 2022;386:556-67. [Crossref] [PubMed]
32. Schedin TB, Borges VF, Shagisultanova E. Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition. Int J Breast Cancer 2018;2018:7835095. [Crossref] [PubMed]
33. Montemurro F, Di Cosimo S, Arpino G. Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications. Ann Oncol 2013;24:2715-24. [Crossref] [PubMed]
34. Montemurro F, Rossi V, Cossu Rocca M, et al. Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2-positive advanced breast cancer patients. Cancer 2012;118:17-26. [Crossref] [PubMed]
35. Wang YC, Morrison G, Gillihan R, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers--role of estrogen receptor and HER2 reactivation. Breast Cancer Res 2011;13:R121. [Crossref] [PubMed]
36. Xia W, Bacus S, Hegde P, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A 2006;103:7795-800. [Crossref] [PubMed]
37. Collins DC, Cocchiglia S, Tibbitts P, et al. Growth factor receptor/steroid receptor cross talk in trastuzumab-treated breast cancer. Oncogene 2015;34:525-30. [Crossref] [PubMed]
38. Buzdar AU, Suman VJ, Meric-Bernstam F, et al. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol 2013;14:1317-25. [Crossref] [PubMed]
39. Tung NM, Zhao F, DeMichele A, et al. Predicting pathologic complete response (pCR) from clinicopathologic variables and HER2DX genomic test in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): Secondary results from the EA1181/CompassHER2 pCR trial. J Clin Oncol 2025;43:501.
40. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013;24:2278-84. [Crossref] [PubMed]
41. Griguolo G, Serna G, Pascual T, et al. Immune microenvironment characterisation and dynamics during anti-HER2-based neoadjuvant treatment in HER2-positive breast cancer. NPJ Precis Oncol 2021;5:23. [Crossref] [PubMed]
42. Malorni L, Tyekucheva S, Zamagni C, et al. Abstract RF1-02: Palbociclib plus letrozole versus weekly paclitaxel, both in combination w/ trastuzumab plus pertuzumab, as neoadjuvant treatment for patients w/ HR+/HER2+ early breast cancer: primary results from the randomized phase II TOUCH trial (IBCSG 55-17). Clin Cancer Res 2025;31:RF1-02. [Crossref] [PubMed]
43. Byrd DR, Brookland RK, Washington MK, et al. AJCC cancer staging manual. 8th ed. Amin MB, Edge SB, Greene FL, editor. New York: Springer; 2017.
44. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164-72. [Crossref] [PubMed]
45. Spring LM, Fell G, Arfe A, et al. Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis. Clin Cancer Res 2020;26:2838-48. [Crossref] [PubMed]
46. Broglio KR, Quintana M, Foster M, et al. Association of Pathologic Complete Response to Neoadjuvant Therapy in HER2-Positive Breast Cancer With Long-Term Outcomes: A Meta-Analysis. JAMA Oncol 2016;2:751-60. [Crossref] [PubMed]
47. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer:National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24:2019-27. [Crossref] [PubMed]
48. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 1997;15:2483-93. [Crossref] [PubMed]
49. Shien T, Shimizu C, Seki K, et al. Comparison among different classification systems regarding the pathological response of preoperative chemotherapy in relation to the long-term outcome. Breast Cancer Res Treat 2009;113:307-13. [Crossref] [PubMed]
50. Kuerer HM, Valero V, Smith BD, et al. Selective Elimination of Breast Surgery for Invasive Breast Cancer: A Nonrandomized Clinical Trial. JAMA Oncol 2025;11:529-34. [Crossref] [PubMed]
51. Nguyen TT, Hoskin TL, Day CN, et al. Decreasing Use of Axillary Dissection in Node-Positive Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. Ann Surg Oncol 2018;25:2596-602. [Crossref] [PubMed]
52. Cabioglu N, Koçer HB, Karanlik H, et al. De-Escalation of Nodal Surgery in Clinically Node-Positive Breast Cancer. JAMA Surg 2025;160:257-66. [Crossref] [PubMed]
53. Limberg JN, Jones T, Thomas SM, et al. Omission of Axillary Lymph Node Dissection in Patients with Residual Nodal Disease After Neoadjuvant Chemotherapy. Ann Surg Oncol 2024;31:8813-20. [Crossref] [PubMed]
54. Wong SM, Weiss A, Mittendorf EA, et al. Surgical Management of the Axilla in Clinically Node-Positive Patients Receiving Neoadjuvant Chemotherapy: A National Cancer Database Analysis. Ann Surg Oncol 2019;26:3517-25. [Crossref] [PubMed]
55. Montagna G, Mrdutt MM, Sun SX, et al. Omission of Axillary Dissection Following Nodal Downstaging With Neoadjuvant Chemotherapy. JAMA Oncol 2024;10:793-8. [Crossref] [PubMed]
56. Laws A, Dillon K, Kelly BN, et al. Node-Positive Patients Treated with Neoadjuvant Chemotherapy Can Be Spared Axillary Lymph Node Dissection with Wireless Non-Radioactive Localizers. Ann Surg Oncol 2020;27:4819-27. [Crossref] [PubMed]
57. Mamounas EP, Bandos H, White JR, et al. Omitting Regional Nodal Irradiation after Response to Neoadjuvant Chemotherapy. N Engl J Med 2025;392:2113-24. [Crossref] [PubMed]
58. Mitchell MP, Shaitelman SF, Smith BD, et al. Feasibility of breast conserving surgery alone in HER2-positive exceptional responders to neoadjuvant systemic therapy. Eur J Surg Oncol 2024;50:108613. [Crossref] [PubMed]