As antibody-drug conjugates (ADCs) and precision medicine continue to develop, breast cancer is entering a new era of treatment. At the 2024 CSCO Annual Conference, Dr. Jian Zhang from Fudan University Shanghai Cancer Center and Dr. Nadia Harbeck from LMU University Hospital, Munich,Germany engaged in a deep discussion about the latest developments in breast cancer treatment. The two professors shared insights into the remarkable efficacy and safety management strategies of ADC drugs in treating HR+ advanced breast cancer patients, while also exploring the critical role of genetic testing in guiding individualized treatment. This dialogue not only reveals the global cutting-edge trends in breast cancer treatment but also provides valuable guidance for future clinical practice, leading the field towards more precise and individualized treatment approaches.

Dr. Jian Zhang: It is a great honor to have Dr. Nadia Harbeck join us for this interview. First, let me introduce Dr. Nadia Harbeck. She is director of the Breast Center and holds the chair for Conservative Oncology at the Dept. of OB&GYN, LMU University Hospital, Munich, Germany.She also heads the Oncological Therapy & Clinical Trials Unit, Dept. OB&GYN and the Center for Hereditary Breast and Ovarian Cancer at LMU University Hospital, Munich. She is a Steering Committee Member of the Munich Comprehensive Cancer Center (CCCMunich LMU). Moreover, she served on the IRB of the LMU Medical Faculty. Professor Harbeck is highly respected, especially in the field of breast cancer treatment. We have a few questions for you. The 2024 ESMO conference has just concluded. What new findings or significant research results regarding ADCs in the treatment of HR+ advanced breast cancer patients caught your attention?

Dr. Nadia Harbeck: At the recent ESMO conference in Barcelona, we saw updated results from the DESTINY Breast-06 (DB-06) study. Although the results from different laboratories were not perfect, they showed a good level of consistency. Therefore, it is recommended that patients with HER2 0 tumors undergo retesting, as there may be subtle differences in expression, particularly in detecting ultra-low HER2 levels, where tumor cells express HER2 at less than 10%. In about 60% of HER2 (0) cases, the central laboratory in the DB-06 study identified HER2 low expression. We also observed some noteworthy patient-reported outcomes (PROs) indicating that patients in the T-DXd group were able to maintain their quality of life. Thus, I believe it is safe to use this drug for early HR-positive/HER2 low breast cancer.

Dr. Jian Zhang: Indeed, as Professor Harbeck mentioned, the DB-06 study is highly significant. The data suggests that the quality of life (QOL) of patients did not deteriorate. At the 2024 ESMO conference, two pieces of DB-06 data were presented as LBA, with Professor Hu Xichun reporting the PRO data. In your opinion, what is the significance of publishing PRO data for patients undergoing treatment?

Dr. Nadia Harbeck: Yes, PRO data is important for patients. Especially when using new drugs, we may see side effects, such as hematologic toxicities from T-DXd. If medical centers do not implement appropriate preventive measures, patients could experience gastrointestinal toxicity as well. Asking patients about their experience is crucial. The overall quality-of-life data from the DESTINY series of studies shows that T-DXd treatment maintains patient quality of life. Although patients may experience nausea and vomiting, we use a triple antiemetic regimen similar to chemotherapy, while some centers use a two-drug antiemetic approach. Over time, if patients tolerate treatment well, we may consider dose reduction, making PRO data critical for understanding patient outcomes. Additionally, based on the DESTINY Breast-04 data, we see that patient pain has decreased, which was also observed in DB-06. This reassures us about the drug’s effectiveness in alleviating symptoms.

Dr. Jian Zhang: In controlling gastrointestinal toxicity, we still face challenges, even when using three to four antiemetics. How do you manage such patients in your clinical practice? Do you reduce the T-DXd dose or extend the dosing cycle to manage side effects?

Dr. Nadia Harbeck: We generally follow the drug label’s recommendations. We start with a triple antiemetic regimen, and for long-term patients who tolerate the treatment well, we may try dose reduction while maintaining close communication with the patient. If patients encounter issues, dose reduction is an option. We’ve used this approach with other drugs as well. However, it’s difficult to generalize because, in some registrational trials, patients who didn’t receive antiemetics managed well. It really depends on individual patient tolerance, and we learn more about their response once treatment starts.

Dr. Jian Zhang: I agree, we can assess and judge before treatment. In some cases, we may consider dose reduction at the start if we anticipate issues. Next, for HR+ advanced breast cancer patients progressing after first-line CDK4/6 inhibitor treatment, would you opt for cross-line CDK4/6 inhibitor use, ADC drugs, or other targeted treatments like PAM pathway inhibitors?

Dr. Nadia Harbeck: In Germany, we have access to all available targeted drugs for such cases. For first-line treatment, we typically test for PIK3CA, ESR1 mutations, BRCA status, and recently, AKT mutations. When patients progress, this information helps guide the next targeted treatment. However, existing data shows that if patients progress within six months of CDK4/6 inhibitor treatment, further endocrine-based therapy is not particularly beneficial. In such cases, we can consider PIK3CA or AKT inhibitors to exclude endocrine resistance. Otherwise, I would lean towards chemotherapy. ADC drugs are not yet available for first-line treatment, but I hope that, based on DB-06 results, T-DXd will be approved. Otherwise, we will use chemotherapy first and consider ADC drugs for second-line treatment.

Dr. Jian Zhang: In Germany, are the costs of genetic testing covered by insurance?

Dr. Nadia Harbeck: In Germany, if genetic testing is used to guide treatment decisions, such as tests related to tumor biology, it is generally covered by insurance. Genetic testing for hereditary breast cancer is also reimbursable. We are fortunate to have access to all necessary information, and the costs of related medications are covered as well. However, some drugs, like alpelisib, are not yet available in Germany, so we need to apply separately for these treatments.

Dr. Jian Zhang: These indications suggest that tissue samples should be used for testing. Do you also use blood samples for testing? In cases where we detect PI3K mutations in blood samples, it may not mean that we can use PI3K inhibitors. Is this type of testing covered by insurance in Germany?

Dr. Nadia Harbeck: It depends on what you’re testing for. ESR1 mutations are typically acquired due to resistance to aromatase inhibitors and develop over time. Therefore, testing for ESR1 mutations using liquid biopsies after patients have been treated with aromatase inhibitors is reasonable. On the other hand, PIK3CA mutations are usually present in the original tumor, and primary tumor samples were used in the SOLAR-1 trial. As such, early testing is possible and generally covered by insurance. However, we cannot perform multiple NGS tests, so we need to obtain all the necessary information from the submitted sample. ESR1 mutations can be tested multiple times because they evolve over time.

Dr. Jian Zhang: We know that PI3K/AKT/PTEN statuses tend to remain stable before and after treatment, especially during endocrine therapy. In contrast, ESR1 mutations are usually acquired. When do you think is the best time to perform NGS testing—during first-line treatment or after treatment? In clinical practice, obtaining results from blood samples can take time, and some patients become anxious. How do you handle this in your practice?

Dr. Nadia Harbeck: In our clinical practice, we submit tumor tissue samples during CDK4/6 inhibitor treatment. After treatment begins, we assess multiple biomarkers, except ESR1 mutations. For ESR1 mutations, we test at the time of disease progression to ensure we have the latest information on tumor mutations. This test, when performed as a liquid biopsy, is reimbursable.

Dr. Jian Zhang: That’s an important insight for guiding our clinical practice. The final question is about the safety concerns of ADC drugs, which are crucial in the treatment of HR+ advanced breast cancer. What are the main side effects of common ADC drugs, and could you share your clinical experience in managing these adverse reactions?

Dr. Nadia Harbeck: We’ve observed that both T-DXd and sacituzumab govitecan (SG) can cause hematologic toxicity, and we usually don’t conduct primary prophylaxis. If patients show signs of toxicity before the eighth day of dosing, we might consider secondary prophylaxis. Gastrointestinal toxicity can also occur, so I believe it’s important to start with antiemetic medication according to local clinical practice, whether it’s a two- or three-drug antiemetic regimen.

For T-DXd, interstitial lung disease (ILD) monitoring is crucial. We must remind patients to seek immediate medical attention if they experience symptoms like cough or shortness of breath, even if it’s late at night, and to get a lung CT scan immediately. If there’s any doubt but no pulmonologist is available, it’s safer to initiate steroids until further evaluation can be done. Responding quickly to ILD symptoms is essential. Additionally, these drugs have strong efficacy, especially T-DXd, which can be used long-term but may cause fatigue. We must discuss lifestyle adjustments with patients to help manage fatigue, and we should consider dose modifications if necessary.

Dr. Jian Zhang: We’ll be discussing this topic further this afternoon. In clinical practice, have you considered rechallenging patients with grade 2 or 3 ILD? If so, what were the outcomes for these patients?

Dr. Nadia Harbeck: We haven’t conducted rechallenges in such patients. My experience comes primarily from clinical trials, where we only rechallenged patients with grade 1 asymptomatic ILD, identified through CT scans, who recovered within a month. For grade 3 ILD, I would be very cautious and wouldn’t recommend rechallenge. However, more data is needed, particularly from registrational databases, to evaluate whether patients with rapidly recovering grade 2 ILD could be rechallenged.

At the ESMO conference, we saw data from a French team whose registry showed that ILD tends to occur early, and prior ILD is a significant risk factor. So, rechallenging such patients should only be done in very controlled settings. However, we have had patients who developed ILD early with everolimus but later tolerated T-DXd relatively well. Still, such cases should be limited to patients who fully understand the treatment process and are willing to seek prompt medical attention if needed.

Dr. Jian Zhang: Indeed, for highly selective patients, rechallenge might be an option. Professor Harbeck’s insights have been incredibly valuable for us. That concludes all my questions. Thank you again, Professor Harbeck, for providing such valuable experiences, which will have a significant impact on our clinical practice. Thank you again!

Dr. Jian Zhang

Chief Physician, Doctoral Supervisor Director, Phase I Clinical Research, Fudan University Shanghai Cancer Center Deputy Director, Department of Oncology, Fudan University Shanghai Cancer Center (Fujian) Chairman, Tumor Drug Clinical Research Committee, Chinese Association of Medical Education Chairman, Tumor Prevention and Clinical Research Committee, China Elderly Care Association Chairman, Breast Academic Alliance of Yangtze Scholars Vice-Chairman, Shanghai Anti-Cancer Association, Breast Cancer Committee, Chinese Anti-Cancer Association

Dr. Nadia Harbeck

Director, LMU University Hospital, Munich,Germany Head of Oncology and Clinical Trials, LMU University Hospital, Munich,Germany