Antibody–Drug Conjugates in Breast Cancer: Ascent to Destiny and Beyond—A 2023 Review

Round 1

Reviewer 1 Report

This manuscript is a review of clinical and preclinical antibody-drug conjugates (ADCs) targeting breast cancer. While the aim is intriguing and the content well written, I find significant concerns that need to be addressed.

Firstly, similar reviews already exist in the public domain. The difference between your manuscript and these needs to be clearly delineated. Here are some examples (but not limited to)

 "Antibody-Drug Conjugates for Breast Cancer", Oncol Res Treat (2022) 45 (1-2): 26-36.

"The evolving therapeutic landscape of antibody-drug conjugates in breast cancer", https://doi.org/10.1080/14737140.2022.2147510

"Antibody-Drug Conjugate Revolution in Breast Cancer: The Road Ahead," https://doi.org/10.1007/s11864-023-01072-5

 

I strongly recommend that the authors include a section on current challenges with ADCs. What are the characteristic irreversible and reversible toxicities in patients in clinical trials? How do this correlate with animal studies in preclinical trials? And what are the potential ways to overcome them? These aspects should be addressed in your manuscript.

 

The authors should also discuss some of the advances in preclinical ADCs. One notable one is the establishment of site-specific ADC manufacturing. Site-specific modification could potentially improve the chemistry, manufacturing, and control (CMC) aspects of ADCs and increase the therapeutic index. These points should also be included and I propose to cite the following references:

 

For the advantage of ADC analysis by site-selective modification: "Anal. Chem. 2019, 91, 20, 12724-12732"

For the advantage of the therapeutic index by site-selective modification: "Nature Biotechnology 2008, 26, 925-932"

 

In its current form, this manuscript does not differ significantly from existing reviews. A thorough exploration of the current challenges and recent advances in ADCs, coupled with a clear delineation of how the authors’ work differs from others, will make your manuscript much more robust and impactful.

 I look forward to the revisions.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

In this review, the authors summarized several ADCs developed for breast cancer treatment including trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG) and other emerging agents. They recapitulated the role of ADCs in breast cancer and discussed the opportunities and challenges. Furthermore, this review discussed future research directions to facilitate target selection, combination therapy strategies, and aim to improve drug safety. The authors anticipate a new era of breast cancer treatment is on the horizon. Overall, this review is very helpful, but there are still two minor issues to be addressed before its acceptance.

Minor comments:

1.    The authors mentioned that T-DXd demonstrated an impressive survival benefit as compared to T-DM1 in the second-line treatment of HER2+ breast cancer. If possible, could the authors provide the potential reason for this advantage of T-DXd in the discussion section, which will be helpful in future directions of ADC development?

2.  Please correct a spelling mistake on page 5, line 187: " included an ultra-low HER2 classification (HER2 IHC >0 and ICH<1+) "

Quality of English language is fine, but please check spelling mistakes carefully.

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I recommend accepting the present form for publication.