In the first article of a 2-part series, Virginia G. Kaklamani, MD, discussed her approach to biomarker testing and treatment sequencing for patients with hormone receptor–positive, HER2-negative metastatic breast cancer.
CASE SUMMARY
Two Years After Completing Adjuvant Therapy
After 16 Months on Treatment
After 10 Months on Treatment
After 8 Months on Treatment
Targeted Oncology: What are some of the reasons to biopsy a patient like this?
VIRGINIA G. KAKLAMANI, MD: One of the reasons why I get a biopsy is because that'll help me figure out how the tumor is evolving. What is the ER doing, what is the PR doing, and what is the HER2 doing? Because, in some cases, the tumor changes and what if it changes from positive to triple negative? [In that case], you may want to use a totally different treatment combination. [In this case after more biomarker testing], treatment would be given with sacituzumab govitecan-hziy [Trodelvy], per the National Comprehensive Cancer Network guidelines.1 Sacituzumab govitecan is a category 1 recommendation because of the improvement in overall survival [in this patient population], but this isn't the only option.
How does more biomarker testing affect your treatment decisions?
The more you test, the more likely you are to find what you're looking for. So the question is, how much are you planning on testing [the patient]? But this also points to whether we think that fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd] is going to work in this HER2 ultra-low category, because [most of] these ER-positive tumors are not going to be completely 0. There's few that have absolute 0 staining, and pathologists now are more prone to looking at these 0 to 1+ [levels], and they'll call them 1+ because they're afraid to call them 0, the same way when there were 1+ or 2+ they'd call them 2+, so that they could get a FISH test to make sure it wasn't HER2 positive. They're guided by our treatments for better or worse, but I think for better in some ways.
What is your approach to sequencing antibody-drug conjugates (ADCs)? Would you alternate between an ADC and chemotherapy for a patient case like this?
[There are] no clinical trial data suggesting that this approach doesn't produce any better outcomes than sequencing 1 ADC after the other. The resistance mechanisms to these ADCs are quite complicated, as there's resistance to the receptor with the emergence of HER2 mutations, TROP2 mutations, and resistance to the payload.2 Both payloads are Topo-I inhibitors, but they're different still. So conceivably, [the patient] may have resistance to 1 mutation but not resistance to the other. People are working hard to try to figure out the resistance mechanisms [to these therapies], and hopefully at some point we'll be able to have that [information] available, so that we can determine which drug to use next.
Please describe datopotamab deruxtecan (Dato-DXd) and its role in this patient population.
Dato-DxD is basically an TROP2-directed antibody with the exact same payload as T-DXd. It's a stable linker and it has a very different safety profile from sacituzumab govitecan. The trial [behind this therapy] was the phase 3 TROPION-Breast01 trial [NCT05104866] for patients with HR-positive, HER2-negative breast cancer—they also could have had HER2 low breast cancer—who had 1 or 2 prior lines of chemotherapy were randomly assigned to either Dato-DXd or investigators choice of chemotherapy.3
References:
1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2024. Accessed March 15, 2024. https://tinyurl.com/mthnuyww
2. Chang HL, Schwettmann B, McArthur HL, Chan IS. Antibody-drug conjugates in breast cancer: overcoming resistance and boosting immune response. J Clin Invest. 2023;133(18):e172156. doi:10.1172/JCI172156
3. Bardia A, Jhaveri K, Kalinsky K, et al. TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer. Future Oncol. 2023. doi:10.2217/fon-2023-0188
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