Analyzing ADC Treatment Sequencing in Advanced Breast Cancer


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.


  • A 60-year-old woman with a history of pT1cN1 estrogen receptor (ER) and progesterone receptor (PR) positive HER2 non-amplified (immunohistochemistry [IHC] score of 1+, fluorescence in situ hybridization [FISH] negative) had invasive ductal carcinoma and high genomic risk (OncotypeDX RS 35).
  • First, she was treated with surgery and adjuvant dose dense chemotherapy, followed by aromatase inhibitor therapy for 10 years.

Two Years After Completing Adjuvant Therapy 

  • The patient presented with persistent rib pain.
  • Fludeoxyglucose (FDG) 18F PET/CT scan demonstrated multiple FDG avid lytic osseous metastases and suspicious appearing FDG avid intrathoracic and intra-abdominal lymph nodes​.
  • A pelvic lymph node biopsy demonstrated adenocarcinoma consistent with her primary breast cancer; ER 80%, PR 20%, HER2 0 ​
  • Next-generation sequencing (NGS) detected a pathogenic hot spot mutation in PIK3CA and no other alterations.
  • The patient was treated with first-line letrozole and ribociclib (Kisqali)​.

After 16 Months on Treatment

  • The patient developed disease progression with enlarging and new involvement of intra-thoracic and intra-abdominal lymph nodes.
  • Treatment was changed to second-line fulvestrant plus alpelisib.

After 10 Months on Treatment

  • Disease progressed further with new lytic bone metastases and a new liver lesion.
  • Biopsy report of liver specimen reported ER 60%, PR 0, HER2 0.
  • NGS revealed no new mutations.
  • Treatment was changed to third-line capecitabine.

After 8 Months on Treatment

  • The patient developed disease progression with enlarging lymph nodes and enlarging liver metastasis​.
  • Liquid biopsy showed detectable circulating tumor DNA, but no new mutations.

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.

Virginia G. Kaklamani, MD​

Professor of Medicine

University of Texas Health Science Center San Antonio

San Antonio, TX

Virginia G. Kaklamani, MD​

Professor of Medicine

University of Texas Health Science Center San Antonio

San Antonio, TX

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


1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 2.2024. Accessed March 15, 2024.

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

Related Videos
Video 7 - "Unmet Needs and Future Directions in HER2+ Breast Cancer"
Video 6 - "Current Approaches to Treatment Sequencing in HER2+ Breast Cancer"
Video 5 - "Exciting Developments in HER2+ Breast Cancer"
Video 4 - "KATHERINE: Adjuvant T-DM1 vs Trastuzumab for Residual Invasive HER2+ Breast Cancer"
Video 3 - "APHINITY Trial: Pertuzumab for Patients with HER2+ Breast Cancer"
Rebecca A. Shatsky, MD, an expert on breast cancer
Rebecca A. Shatsky, MD, an expert on breast cancer
Related Content