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Clinical Cases: Hormone-Receptor Positive, HER2-Positive, Metastatic Breast Cancer 

In this clinical case discussion from the 2023 Best of Breast Conference, our expert panel highlights the very latest in treatment.


Dr Reshma Mahtani, Miami Cancer institute

Dr Komal Jhaveri, Memorial Sloan Kettering Cancer Center

Dr Ruta Rao, Rush University Medical Center

Dr Sunil Badve, Emory University

Dr Cynthia Ma Washington University St. Louis

Dr Kristina Mirabeau Beale, GenesisCare USA

Our expert panel discussions consider hypothetical patients, and are intended to increase understanding, and stimulate discussion with your cancer care team, but not to replace the advice of your treating physician.  Many clinical factors impact cancer care, and your course of treatment and outcomes may differ from the cases considered here.

The expert panel, moderated by Dr Reshma Mahtani from Miami Cancer Institute, considered the case of 58-year-old woman who presented with a breast mass that she neglected for 1 year, who recently developed low back pain. Her CT scan showed a mass in her breast that, upon biopsy, showed it to be positive for estrogen receptor (ER), progesterone receptor (PR) and another receptor, human epidermal growth factor receptor 2, or HER2. Her breast tumor was thus classified as hormone receptor positive (HR+), HER2+, invasive ductal carcinoma breast cancer. Furthermore, there was suspected spread to the lymph nodes in her axilla (armpit) and her CT scan showed a single lesion at one of her lumbar vertebrae, L3, that was likely the source of her back pain. It was therefore suspected that her breast cancer had spread to single site in her spine (Stage IV metastatic disease). The panel thus first discussed treatment options in the setting of a patient with HR+, HER2+, oligometastatic disease.

1st Line Treatment

Most panelists agreed that they would offer “curative-intent” systemic therapy for this patient as a means to palliate the symptoms (assuming her lesion in the spine was indeed proven to be breast cancer). The tumor itself would not be removed and systemic therapy and radiation therapy would be offered to alleviate the pain of the metastatic lesion in her spine.

With regard to the possible use of radiotherapy (RT) in this patient, Dr Kristina Mirabeau Beale, a radiation oncologist from Genesis Care USA, reviewed data from the NRG-BR002 study. This study examined the use of symptom-directed, targeted RT in combination with standard of care (SOC) systemic therapy, versus a total ablation of all metastases using high dose RT with SOC systemic therapy, in patients with oligometastatic breast cancer with fewer than 4 metastatic sites on imaging. The results of the trial showed no significant difference in progression-free survival (PFS) or overall survival (OS) in these patients when comparing the SOC with adding ablative RT to the SOC treatment. She added however, that research continues to examine whether there may be specific subgroups of metastatic breast cancer patients that might benefit from such therapy.

2nd Line Treatment

The case continued, with the patient receiving a first line treatment with chemotherapy (docetaxel) and HER2-targeted therapy (trastuzumab and pertuzumab) which alleviates her back pain for close to 2 years. She returns, however, now having developed a recurrence of her back pain and a cough. Her imaging results show that her cancer has progressed in the bone as well as in the lungs. Upon biopsy of the lung lesion, it is confirmed to be HR+/HER2+ breast cancer once again.

The panelists reviewed the options for additional (2nd line) treatment in this patient, and considered whether the presence of a cough (likely a result of the cancer having spread to her lungs) would impact that choice. Most panelists agreed that trastuzumab-deruxtecan, or T-DXd would be an option for this patient, based on the results of the DESTINY Breast 03 trial. T-DXd is an antibody-drug conjugate, or ADC, that consists of an antibody designed to target HER2 on breast cancer cells, linked to a chemotherapy drug (the “payload”), such that it is more specifically targeted the breast cancer cells.

In this regard, Dr Ruta Rao, an oncologist from Rush University Medical Center, discussed updated results from the DESTINY Breast03 trial, which compared the efficacy of T-DXd with that of a different HER2-targeted ADC, T-DM1, in patients with inoperable metastatic HER2 positive breast cancer (prior to the trial, T-DM1 had been the standard of care for such patients). The results showed, at 24 months, a significant difference in OS for patients treated with T-DXd (2-year OS, 77.4%) versus those treated with T-DM1 (2-year OS, 69.9%). In addition, she noted results for the primary endpoint of PFS, which was improved by 4-fold (median PFS, 28.8 versus 6.8 months). The results thus favor the use of T-DXd as a 2nd line option in this patient, and the panelists noted this approach is supported by current treatment guidelines.

Dr Cynthia Ma, an oncologist from Washington University St. Louis, reviewed the principal toxicities of T-DXd, primarily nausea, fatigue, alopecia, vomiting, and reduction in blood cell counts (neutropenia and anemia). Some panelists noted that some key adverse events (AEs) like alopecia, while important to discuss with patients before starting therapy, actually occurred at a lower frequency, or more sporadically in everyday practice, as compared to the clinical trial. Dr Ma noted that interstitial lung disease, or ILD, is an important event to monitor for in patients on T-DXd, with 15.2% of patients developing some grade of ILD on T-DXd, compared with 3.1% on T-DM1. She reviewed detailed guidance for monitoring and managing ILD in patients on T-DXd which has been established. She noted the importance of monitoring for new or worsening lung symptoms in patients on T-DXd, which might include symptoms like shortness of breath, cough, or fever. Further evaluation is needed for patients with suspected ILD, and the dosing T-DXd will need to be interrupted if patients are confirmed to have any grade of ILD. Permanent discontinuation of T-DXd may also be necessary if Grade 2 or higher ILD develops, although the panel noted that overall ILD necessitating discontinuation of T-DXd was an infrequent occurrence in their everyday practice. The panelists were also in agreement that, whereas monitoring for ILD would be important in this patient, their treatment choice would not be impacted by the presence of a cough and/or lung metastases. Dr Komal Jhaveri, an oncologist from Memorial Sloan Kettering Cancer Center, also noted that, based on the available data to date, the presence of lung metastases does not appear to be a predisposing factor for developing ILD while on T-DXd.

3rd Line Treatment: Brain Metastases

The panel then continued the case scenario, in which the patient’s cancer remained controlled in the 2nd line setting while on T-DXd, but now two lesions in her brain are discovered as an incidental finding upon imaging her head after a fall. The findings are thus consistent with metastatic disease in the brain that is not symptomatic or impairing the patient’s day-to-day activities. The question was posed to the panel as to whether her systemic therapy should be changed, as well as what the local therapy options are for the lesions in the brain (for example, radiotherapy) and whether they would offer the patient such therapy.

Dr Ma first reviewed the update in treatment guidelines for patients with brain metastases, which state that HER2-directed systemic therapy should not be changed upon diagnosis of brain metastases if the patient’s systemic disease remains well controlled, as in the present example. By comparison, if patients do have systemic disease that is progressing when brain metastases are discovered, a change in therapy should be considered.

Dr Ma then reviewed data from the HER2 CLIMB trial, which established the regimen of tucatinib, a tyrosine kinase inhibitor (TKI) drug, with capecitabine (chemotherapy) and trastuzumab (HER2-directed therapy) for patients with stable, previously treated, or untreated brain metastases that did not require immediate therapy (i.e., asymptomatic disease, such as in the present case example). The results of the trial showed a benefit of adding tucatinib to the regimen over placebo, both in terms of PFS (7.8 vs. 5.6 months) and OS (21.9 vs. 17.4 months). The results were similar in the overall population, as well as in the subset of patients with brain metastases. A higher proportion of patients with active brain metastases also had a confirmed response with the addition of tucatinib to the regimen (47% vs. 20%) and central nervous system PFS was higher with tucatinib in these patients (9.5 vs. 4.1 months).

While acknowledging the option for systemic therapy based on the HER2 CLIMB data, panelists agreed about the need to engage both neurosurgical specialists and radiation oncologists in the multidisciplinary management of this patient. Dr Mirabeau Beale noted that, based on current guidelines for patients with limited disease, the use of stereotactic RT is preferred over the use of whole brain radiation (WBRT), which can result in significant side effects such as fatigue and cognitive dysfunction. The size of the lesions, the presence of edema, and the number of lesions are all considerations for stereotactic RT in this regard.

‘HER2-Low’ Disease: Another Consideration

The panel also considered a variation in the case whereby the same patient with metastatic disease was HR+, but in which the primary tumor specimen had a lower expression of HER2, termed “HER2-Low” disease. The question was then posed whether the panelists would still use T-DXd to treat in the 2nd line.

Dr Sunil Badve, a pathologist from Emory University, reviewed the criteria for HER2 Low disease. He noted that there may be different levels of HER2 expression observed based upon many factors such as prior treatment received (for example, endocrine therapy versus no endocrine therapy) and based on the location and variation in where the biopsy sample was taken (tumor heterogeneity). He further noted that, while there may be some biological differences among tumors that express lower or higher HER2 levels which remain to be studied, this does not at present preclude the use of HER2-directed therapies like T-DXd. As such, the panelists were in uniform agreement that, despite a HER2-Low status, they would still consider T-Dxd treatment an option, because patients with any degree of HER2 expression in their tumors were eligible to be included in the trial of T-DXd. Importantly, before T-DXd would be considered for this variation in the case, the patient would have had to have exhausted other treatment options such as endocrine therapy and other targeted treatment options in the metastatic setting such as CDK 4/6 inhibitor drugs.

Dr Rao noted that the efficacy of T-DXd may also be related to the so-called “bystander effect” which has been observed, whereby the binding and killing of cells with T-Dxd and subsequent release of the cancer-killing payload also results in the killing of the surrounding cells that might express lower levels of the HER2 target. She reviewed the evidence for the efficacy of T-DXd over T-DM1 which was shown in the pivotal trial, DESTINY-Breast04, and favored the use of T-DXd in both PFS and OS in HER2-Low patients.


Dr Mahtani concluded by summarizing the overall treatment plan for patients with primary HR+/HER2+ metastatic breast cancer. She noted that while some regimens, such as the initial first-line regimen of taxane/trastuzumab/pertuzumab (THP) remain in place, emergent data from trials like DESTINY-Breast03 and HER2 CLIMB have established new regimens in the 2nd line setting, and for patients with brain metastases, respectively. Unanswered questions that remain are how to best sequence all of these therapies to further improve survival, and how to integrate additional drugs and treatment regimens currently under investigation in this setting.

See more from the 2023 Best of Breast Conference here.

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