BCC 2021 | The meaning of residual disease in breast cancer

I was given this, what I think is an interesting topic of the meaning of residual disease. What we’re talking about here is what happens when patients are treated with neoadjuvant therapy, whether they have a pathologic complete response, or whether they have residual disease. What are the implications for that? And I think this has become very important these days because neoadjuvant therapy is now commonly used. In fact, it’s really the standard of care for patients with triple negative breast cancer, with stage II or higher cancers, or HER2-positive stage II or higher cancers. The guidelines from St. Gallen previously have made it very clear that we should be treating patients with that clinical presentation with neoadjuvant therapy. So it’s important that we understand the implications for patients whose cancer responds completely, that is has a pathologic complete response, or does not respond as well and has residual disease after completion of their neoadjuvant treatment.

Now we know from a number of very large studies that having residual disease is prognostic, or the converse, having a pathologic complete response is very prognostic for an individual patient. We know that those patients who have a pathologic complete response have substantially better outcomes than those who do not. Particularly for patients with hormone receptor-negative, HER2-positive cancers and for triple negative cancers, where the prognostic value of pCR is the strongest.

And we also know that patients who have residual disease after neoadjuvant therapy can benefit from escalation of their treatment if they have triple negative or HER2-positive breast cancers. For triple negative breast cancers that have residual disease, adding an adjuvant capecitabine substantially improves outcome, and similarly adding T-DM1 for patients with HER2-positive breast cancers after neoadjuvant therapy who have residual disease also is quite beneficial.

The dilemma or the conundrum here is that it’s certainly prognostic for the individual patient to have a pCR. It does not appear that a new therapy that improves path-CR necessarily improves long-term outcome. And that’s where there’s kind of been some misunderstanding about the significance of pCR. And I think that’s something that we need to keep in mind. There are other roles for using pCR or residual disease as an endpoint. We’re hoping that not only can we use residual disease as a way to identify patients who can escalate therapy.

Conversely, we think it’s potentially useful to take patients who have a pCR and consider de-escalation of therapy. So taking the opposite approach for the patients who have a pCR. And there are now studies underway that are actually testing that hypothesis, taking patients who have early stage breast cancer, particularly HER2-positive breast cancer, treating them with a truncated amount of neoadjuvant chemotherapy and HER2 therapy. And if they have a pCR stopping chemotherapy at that point, and just continuing with HER2 therapies, such as trastuzumab and pertuzumab. And for those patients who don’t have a pCR, then adding additional therapy and potentially even escalating therapy beyond that. So there are now in the United States, a large cooperative group study that’s testing that approach, whether we can use pCR to de-escalate therapy. And there recently was reported at San Antonio last year, a pilot study showing that that approach is actually quite well received by both patients and investigators. And so I think that does bode well for such de-escalation approaches and we need to prove that this does lead to good outcomes and less toxicity than our current standard.

I think lastly, in terms of the importance of residual disease, it can be a window into potential mechanisms of resistance. Intuitively one would expect that residual cancer cells that remain after neoadjuvant therapy are enriched for mechanisms of resistance. And there are now studies underway and that have been completed that are analyzing the genomics and proteomics of the residual cancers to determine what led to the resistance. And I think that’s an approach that will be useful going forward.

And then lastly, I just want to reiterate this misconception about pCR. Again, for an individual patient having a complete response is highly prognostic, but it’s not an end in itself. It’s just a surrogate for favorable outcome. So it does not make sense to intensify therapy just to achieve a pCR. That’s not necessarily going to improve outcomes for a patient and I think that’s something that we as oncologists need to remember that pCR does have limitations and it’s not an end to itself. So I think those were the major messages that we wanted to get across with this presentation.