Case 2

Dr. Chau Dang:

Now we’re going to move on to the adjuvant setting. We just got through discussing how we treat a patient in a neoadjuvant setting. Let’s talk about a patient in the adjuvant setting. Case 2. This is a 45-year-old premenopausal woman with a left-sided clinical T1 N0, ER-negative, PR-negative, HER2-positive breast cancer. She presented with a palpable left breast mass at the 3 o’clock position. She had bilateral mammogram that was completely negative because her breasts are quite dense. But the breast ultrasound MRI did show the left-sided breast cancer. It’s a solid mass measuring 1.1 cm, and there were no abnormal nodes visible.

This is a clinical T1 N0 stage I, and the biopsy of the mass showed it was invasive ductal carcinoma, ER 0%, PR 0%, HER2/neu 2+, but the FISH ratio is amplified at 6.5. At this point, we have a patient who has a clinical stage I breast cancer. Do we send her to surgery with a consideration of TH based on the APT study, or is there a role for neoadjuvant TH here? Thirdly, is there a role for neoadjuvant HP-based chemotherapy with polychemotherapy? Shanu, what are your thoughts about this patient who has a small tumor? Should we just send her to surgery? And what would you offer her if she remains to have a stage I breast cancer?

Dr. Shanu Modi:

As you outlined, for these lower-risk stage I patients, our preference today, given results from the APT trial, is to do upfront surgery. I would choose option A here. In contrast to the first case, this is a patient with a smaller tumor and a better prognosis than the stage II patients. What we’ve shown over time is that as we introduce more effective targeted therapies, we can de-escalate some of the chemotherapy components of our regimens.

That was exactly the rationale behind the APT trial, which really sets the standard for stage I HER2-positive early-stage breast cancer today. This was a study of over 400 patients. It was a straight phase II trial where they enrolled largely stage I, early-stage HER2-positive patients. There was a small number of patients who got on with tumors between 2 and 3 cm. They showed that by de-escalating the polychemotherapy to single-agent, weekly paclitaxel for 12 weeks, in combination with trastuzumab for 1 year, you could retain the long-term efficacy of the regimen and de-escalate the toxicity.

And that’s really become our standard today. We recently saw the 10-year update from the APT trial, and it was really reassuring to see that we are still achieving excellent outcomes for these patients as well as we would with polychemotherapy if we do indirect comparison. The invasive disease–free survival is 91% for all patients. It was fairly similar between ER-positive and ER-negative patients. The breast cancer–specific survival is over 98%. That’s really tremendous to see, and survival is 94% from that update. I think there’s a strong and compelling rationale that we can de-escalate the polychemotherapy in these stage I patients and give them what we call today the TH regimen.

Dr. Chau Dang:

Dr. Elias, would you agree, TH?

Dr. Anthony Elias:

Yes. I think I’ll play devil’s advocate for a moment: one is tempted to consider whether neoadjuvant therapy could be approached in this situation. The major risk of preoperative therapy is that you overtreat somebody, for example. Certainly, if I were going to consider preoperative therapy in a smaller tumor with lower risk, I would not want to subject them to AC followed by THP or TCHP. Those are quite toxic regimens. But the COMPASS trial, for example, gave THP preoperatively and if you got pCR, you did very well. THP is not all that dissimilar from TH. It does have more expense. It does have more diarrhea, in particular, but by and large, it’s not a particularly toxic regimen.

In keeping with the ATEMPT trial and so forth, we could treat this patient with THP or even TH, we don’t have data really on that. Having negative nodes at the time of surgery, as I pointed out, does influence radiation fields of axillary management and so forth, and you have that readout of treatment effect. I could argue that, and I think that’s an area of controversy and discussion and certainly I think it's going to evolve.

Dr. Chau Dang:

Right. Thanks so much. I personally would say that since this is a small tumor and it is operable, most of us would favor surgery upfront, but I hear your point. After the APT trial result, everybody was so excited about it. We were giving it, and there was hair loss that we accepted, but the ATEMPT trial was open to evaluate T-DM1 against TH and looking for clinically relevant toxicity differences. It was powered to look for superiority of T-DM1 over TH. They also looked at efficacy, and we know the efficacy is the same for the two. But it was a negative trial because the toxicity percentages were similar across the two. There were just different toxicities. There is still a desire to use T-DM1. Would you use it here? It’s not standard, so would you consider it?

Dr. Shanu Modi:

I think we are waiting for the day when we have that as an option, frankly. I think most of us would love to use a therapy that has fewer side effects for patients, less hair loss, less neuropathy. There are trade-offs between T-DM1 and TH. But in general, some of the significant long-term toxicities of TH, neuropathy in particular, we may be able to avoid with a drug like T-DM1. Right now, there’s ATEMPT 2.0 that we’re waiting for, where they use a shorter duration of the T-DM1, and maybe that’ll give us the solution we need here for our lower-risk stage I patients.

Dr. Chau Dang:

Thanks, Shanu. Dr. Elias, since you mentioned node positivity, I’m going to ask you this question. The patient did go to surgery. She had her lumpectomy and was upstaged, unfortunately. The tumor was a 1.2-cm invasive ductal carcinoma. It was ER/PR-negative, HER2 3+, but there was a node that was involved with macro metastasis. She was a clinical stage I, but she was upstaged at the time of surgery. Did we miss our boat here in giving dual-antibody therapy? Because normally, we would given HP-based treatment if we knew a patient was at a clinical stage II. In this case, we did not. How would you treat her at this point? Have we lost an opportunity to give her dual-antibody therapy here, Dr. Elias?

Dr. Anthony Elias:

Right. Well, you see, I peeked. I knew that we had this problem with the node, which is why I played devil’s advocate with the previous discussion. We’re now faced with somebody who doesn’t fit the TH eligibility requirements; that was really for node-negative. It did stretch into the T2 N0 range. This would’ve been a T1 N0 and would’ve fit ATEMPT and TH. At this point, for example, we can look at the APHINITY trial, which was fairly recently updated with survival data by Dr. Loibl at ESMO in 2022. That compared standard chemotherapy plus trastuzumab with or without pertuzumab. This was all therapy given postoperatively. The short-term follow-up and, in fact, even the long-term have shown an invasive disease–free survival benefit, which is modest for the addition of pertuzumab to the combination. There was roughly a 5% advantage in invasive disease–free survival at 8.4-year median follow-up.

This was somewhat more in the node-positive group. The overall survival trended toward a survival advantage, but it lost significance in part because of multiple looks at the data, and therefore the P value that was required was .006, which is a fearsome bar to cross. It reached .007 for the node-positive with only a 1.9% advantage—a relatively small level of advantage. Still, I would give this patient TCHP and then as a 45-year-old with no particular risk factors, she would have a low risk for cardiac toxicity, and I certainly could contemplate THP or even TH with AC in the adjuvant setting.

Dr. Chau Dang:

Thank you. It sounds like she was upstaged to node-positive at the time of surgery. In my view, we have an opportunity here to give her a better therapy, meaning HP-based treatment based on APHINITY. Did we really miss the boat? We didn’t give it neoadjuvantly, because she didn’t really qualify for it. You can still improve her long-term outcomes in the adjuvant setting. Shanu, what would you do? We see these cases in the clinic; we’re confident the patient is stage I, is going to remain stage I, and then we find this node. What do you do?

Dr. Shanu Modi:

We see this unfortunately sometimes, and it’s disappointing when our best imaging fails to find these nodes. This was a macro node, so it’s a little puzzling. I think in general, approximately 20% of T1 N0 clinical HER2-positives may get upstaged to a positive node. I think the one thing we should do when we are thinking about using this de-escalated TH and surgery upfront approach is really do dedicated axillary imaging, ultrasound of the axilla in these patients to be as confident as we can that they’re going to have the same stage preoperatively and postoperatively. I don’t think all is lost. We do have great regimens for node-positive early-stage HER2-positive patients with dual blockade. She has the opportunity now to get pertuzumab on the backend. She’ll get it for a year in combination with trastuzumab with polychemotherapy.

Again, in the APHINITY trial, it wasn’t meant to compare the anthracycline vs nonanthracycline or chemo options. Overall, we saw similar outcomes when we looked at the two groups. From my perspective, again, I’d be tempted to give her the TCHP regimen now in the adjuvant setting, given that she’s node-positive. And, just to point out, that was the group that really benefited from the dual pertuzumab and trastuzumab in the adjuvant setting in APHINITY. It was the node-positive patients, and ER- and PR-negative patients both benefited. She fits that population in the APHINITY trial. That’s probably what I would offer in this setting.

Dr. Chau Dang:

Great. I would, too. Absolutely. We’re fortunate to have such good drugs now in the early-stage setting. Our patients are really staying in remission a long time, which is really good news. But, unfortunately, we’re still seeing metastatic HER2-positive breast cancer, but more and more so, we’re seeing de novo metastatic cases.