Antibody Drug Conjugates: a growing field of targeted therapy for breast cancer

The landscape of breast cancer care and how we're working on pushing the targeted treatment movement forward is rapidly changing, especially with antibody drug conjugates (ADCs). 

I like to think of ADCs as targeted missiles. They're essentially composed of antibodies against specific antigens, or targets of interest, and then they're combined with a linker to a chemotherapy payload. It's a way to deliver the chemotherapy in a more targeted manner than traditional chemotherapy, which is an exciting opportunity to allow us to target those patients who otherwise prefer agents that were more difficult to tolerate before this technology was invented. 

This field has grown exponentially in the last 5 to 10 years and has presented multiple new opportunities for research. What is most exciting is that we have new targets for these treatments—new antigens that we can target with novel ADCs.

The NeoSTAR trial evaluated the ADC sacituzumab govitecan (SG), which is used for patients who have earlier stage triple negative breast cancer before surgery. The idea of this is to hopefully spare patients from many of the more toxic effects of traditional chemotherapy, while still providing them precision in terms of the treatment that we're targeting in the body. 

I was involved in the ASCENT trial, which is also notable for precise treatment. It demonstrated the superiority of SG in metastatic triple negative breast cancer, and more recently the US Food and Drug Administration label has been expanded to the metastatic hormone-positive space as well. As we're developing these ADCs and broadening their use, we're able to reach larger patient populations. It's really exciting because we know there's such an appetite among our patients to use these agents, given how effective they can be and, in some situations, less toxic than the standard chemotherapy they would have otherwise gotten. 

The other big category of trials involves another ADC called trastuzumab deruxtecan (TD). Trastuzumab is conjugated against HER2, a breast cancer specific agent, and is combined with the linker, deruxtecan—a very potent chemotherapy payload. TD was initially used in patients who had HER2-positive breast cancer. In fact, trastuzumab, the first half of the drug, was used as an antibody in and of itself in a lot of earlier stage and metastatic cancer for years. We've known about that for a long time. But more recently, with the series of DESTINY trials, we have seen the major impact that TD in HER2 can have compared to other chemotherapy agents and against other ADCs as well. 

What was so exciting about the trials presented in 2022 is that they created a new category of patients called HER2-low. Before, we had always considered patients as HER2-positive or HER2-negative. We now know it's not that binary. We had already known by the way we do the pathology that people can have levels of HER2 expression. HER2-low patients are people who would have been considered HER2-negative before this—but have some HER2 expression. They have what we consider low on a scale of 0 to 3+, typically. Therefore, they're 1+ or 2+, not 0, and not 3+, because that would be considered HER2-positive. It's a little more complicated because when it's triple 2-positive, they could also do a back-up test, if a patient is positive on that, they are considered as HER2-positive. 

There is now a new category of HER2-low patients who were also shown to have a tremendous improvement benefit with TD; this new category of patients could be candidates for this treatment, although they would never have been used for HER2 targeting before. These agents can be so effective that it's even causing us to rethink our classifications of disease. 

Some of what we're working on right now is specifically looking at how patients are resistant to these agents; that's one of our major focuses as Mass General. We know these treatments are highly effective, but unfortunately, they don't last forever. Very few of these cancer treatments do, because as we know, cancer has this remarkable ability to evolve resistance to agents that we use. The amazing thing about ADCs is they've extended (in some cases) overall survival for patients, which is fantastic. But as I said, we know that they are not lasting forever. Part of what we're involved in with that clinical and research setting is to look at patients who've had success with these agents and ultimately progressed, and then figure out what changed before and after treatment (down to the single cell or genetic level) in order to continue expanding use of these treatments, extending use of the treatments, and making them more effective for more patients. 

The landscape of breast cancer care and how we're working on pushing the targeted treatment movement forward is rapidly changing, especially with antibody drug conjugates (ADCs). 

I like to think of ADCs as targeted missiles. They're essentially composed of antibodies against specific antigens, or targets of interest, and then they're combined with a linker to a chemotherapy payload. It's a way to deliver the chemotherapy in a more targeted manner than traditional chemotherapy, which is an exciting opportunity to allow us to target those patients who otherwise prefer agents that were more difficult to tolerate before this technology was invented. 

This field has grown exponentially in the last 5 to 10 years and has presented multiple new opportunities for research. What is most exciting is that we have new targets for these treatments—new antigens that we can target with novel ADCs.

The NeoSTAR trial evaluated the ADC sacituzumab govitecan (SG), which is used for patients who have earlier stage triple negative breast cancer before surgery. The idea of this is to hopefully spare patients from many of the more toxic effects of traditional chemotherapy, while still providing them precision in terms of the treatment that we're targeting in the body. 

I was involved in the ASCENT trial, which is also notable for precise treatment. It demonstrated the superiority of SG in metastatic triple negative breast cancer, and more recently the US Food and Drug Administration label has been expanded to the metastatic hormone-positive space as well. As we're developing these ADCs and broadening their use, we're able to reach larger patient populations. It's really exciting because we know there's such an appetite among our patients to use these agents, given how effective they can be and, in some situations, less toxic than the standard chemotherapy they would have otherwise gotten. 

The other big category of trials involves another ADC called trastuzumab deruxtecan (TD). Trastuzumab is conjugated against HER2, a breast cancer specific agent, and is combined with the linker, deruxtecan—a very potent chemotherapy payload. TD was initially used in patients who had HER2-positive breast cancer. In fact, trastuzumab, the first half of the drug, was used as an antibody in and of itself in a lot of earlier stage and metastatic cancer for years. We've known about that for a long time. But more recently, with the series of DESTINY trials, we have seen the major impact that TD in HER2 can have compared to other chemotherapy agents and against other ADCs as well. 

What was so exciting about the trials presented in 2022 is that they created a new category of patients called HER2-low. Before, we had always considered patients as HER2-positive or HER2-negative. We now know it's not that binary. We had already known by the way we do the pathology that people can have levels of HER2 expression. HER2-low patients are people who would have been considered HER2-negative before this—but have some HER2 expression. They have what we consider low on a scale of 0 to 3+, typically. Therefore, they're 1+ or 2+, not 0, and not 3+, because that would be considered HER2-positive. It's a little more complicated because when it's triple 2-positive, they could also do a back-up test, if a patient is positive on that, they are considered as HER2-positive. 

There is now a new category of HER2-low patients who were also shown to have a tremendous improvement benefit with TD; this new category of patients could be candidates for this treatment, although they would never have been used for HER2 targeting before. These agents can be so effective that it's even causing us to rethink our classifications of disease. 

Some of what we're working on right now is specifically looking at how patients are resistant to these agents; that's one of our major focuses as Mass General. We know these treatments are highly effective, but unfortunately, they don't last forever. Very few of these cancer treatments do, because as we know, cancer has this remarkable ability to evolve resistance to agents that we use. The amazing thing about ADCs is they've extended (in some cases) overall survival for patients, which is fantastic. But as I said, we know that they are not lasting forever. Part of what we're involved in with that clinical and research setting is to look at patients who've had success with these agents and ultimately progressed, and then figure out what changed before and after treatment (down to the single cell or genetic level) in order to continue expanding use of these treatments, extending use of the treatments, and making them more effective for more patients. 

The landscape of breast cancer care and how we're working on pushing the targeted treatment movement forward is rapidly changing, especially with antibody drug conjugates (ADCs). 

I like to think of ADCs as targeted missiles. They're essentially composed of antibodies against specific antigens, or targets of interest, and then they're combined with a linker to a chemotherapy payload. It's a way to deliver the chemotherapy in a more targeted manner than traditional chemotherapy, which is an exciting opportunity to allow us to target those patients who otherwise prefer agents that were more difficult to tolerate before this technology was invented. 

This field has grown exponentially in the last 5 to 10 years and has presented multiple new opportunities for research. What is most exciting is that we have new targets for these treatments—new antigens that we can target with novel ADCs.

The NeoSTAR trial evaluated the ADC sacituzumab govitecan (SG), which is used for patients who have earlier stage triple negative breast cancer before surgery. The idea of this is to hopefully spare patients from many of the more toxic effects of traditional chemotherapy, while still providing them precision in terms of the treatment that we're targeting in the body. 

I was involved in the ASCENT trial, which is also notable for precise treatment. It demonstrated the superiority of SG in metastatic triple negative breast cancer, and more recently the US Food and Drug Administration label has been expanded to the metastatic hormone-positive space as well. As we're developing these ADCs and broadening their use, we're able to reach larger patient populations. It's really exciting because we know there's such an appetite among our patients to use these agents, given how effective they can be and, in some situations, less toxic than the standard chemotherapy they would have otherwise gotten. 

The other big category of trials involves another ADC called trastuzumab deruxtecan (TD). Trastuzumab is conjugated against HER2, a breast cancer specific agent, and is combined with the linker, deruxtecan—a very potent chemotherapy payload. TD was initially used in patients who had HER2-positive breast cancer. In fact, trastuzumab, the first half of the drug, was used as an antibody in and of itself in a lot of earlier stage and metastatic cancer for years. We've known about that for a long time. But more recently, with the series of DESTINY trials, we have seen the major impact that TD in HER2 can have compared to other chemotherapy agents and against other ADCs as well. 

What was so exciting about the trials presented in 2022 is that they created a new category of patients called HER2-low. Before, we had always considered patients as HER2-positive or HER2-negative. We now know it's not that binary. We had already known by the way we do the pathology that people can have levels of HER2 expression. HER2-low patients are people who would have been considered HER2-negative before this—but have some HER2 expression. They have what we consider low on a scale of 0 to 3+, typically. Therefore, they're 1+ or 2+, not 0, and not 3+, because that would be considered HER2-positive. It's a little more complicated because when it's triple 2-positive, they could also do a back-up test, if a patient is positive on that, they are considered as HER2-positive. 

There is now a new category of HER2-low patients who were also shown to have a tremendous improvement benefit with TD; this new category of patients could be candidates for this treatment, although they would never have been used for HER2 targeting before. These agents can be so effective that it's even causing us to rethink our classifications of disease. 

Some of what we're working on right now is specifically looking at how patients are resistant to these agents; that's one of our major focuses as Mass General. We know these treatments are highly effective, but unfortunately, they don't last forever. Very few of these cancer treatments do, because as we know, cancer has this remarkable ability to evolve resistance to agents that we use. The amazing thing about ADCs is they've extended (in some cases) overall survival for patients, which is fantastic. But as I said, we know that they are not lasting forever. Part of what we're involved in with that clinical and research setting is to look at patients who've had success with these agents and ultimately progressed, and then figure out what changed before and after treatment (down to the single cell or genetic level) in order to continue expanding use of these treatments, extending use of the treatments, and making them more effective for more patients.