This is a postmenopausal patient who underwent routine screening and mammography. She did not come in with any symptoms. Unfortunately, like many of the patients with breast cancer these days, her disease was detected by an abnormality that showed up on the screening mammogram. That, of course, prompted further evaluation with an ultrasound that looks at the breast and looks at the lymph nodes, and there was a suggestion of some abnormal lymph nodes. And then, the patient was appropriately referred for a biopsy and underwent a core biopsy that revealed a diagnosis of breast cancer.

Now, this breast cancer underwent the typical evaluation for both hormone receptors, which in this case were negative, and for HER2, which is standard for any new diagnosis of breast cancer. That revealed that this case is a HER2-positive breast cancer. At this point, we start thinking about what the best treatment approaches are for this patient. We look at the considerations for neoadjuvant therapy, adjuvant therapy, and the guidelines. I think the NCCN [National Comprehensive Cancer Network] guidelines really help us try to figure out what the next best steps are for this patient to take.

When we look at the NCCN guidelines and look at this postmenopausal 56-year-old lady who has a HER2-positive, hormone receptor-negative breast cancer, we look at a couple considerations for neoadjuvant therapy, and she presented with many of those findings. The concurrent considerations for neoadjuvant therapy look at a tumor size greater than 2 cm, and by imaging, her tumor falls into that category.

There&rsquo;s also a suggestion of involvement of lymph nodes, and she did undergo an evaluation of the lymph node at the time of her breast biopsy. That did, unfortunately, reveal there was disease in at least 1 of the lymph nodes. That&rsquo;s a patient who I would typically think of as a good patient for neoadjuvant therapy considerations. I think the guidelines would support that as well, and looking at treatment options, we clearly think about dual HER2-targeted therapy with chemotherapy for the neoadjuvant setting. This particular patient received a recommendation of a taxane and platinum-based regimen with docetaxel/carboplatin given concurrently with Herceptin [trastuzumab] and Perjeta [pertuzumab]. She then underwent surgery following completion of her chemotherapy.

When we look at a patient who comes in post-biopsy, we now have some parameters to start thinking of how we should best approach the patient. This patient clearly had an appropriate workup in terms of an imaging procedure that demonstrated a breast abnormality. She went on to an ultrasound that looked at both the breast and the lymph nodes. And so, we really do want to get a look at thatthe axillary contents&mdash;to start planning the strategy of neoadjuvant or adjuvant therapy, and even have considerations for the surgeon to perform sentinel node evaluation or full axillary bisection. This patient&rsquo;s ultrasound did suggest a reason to biopsy a lymph node, and we have now documented lymph node involvement for this patient. This clearly guides us to the consideration of neoadjuvant therapy in this particular case.

The considerations really are, What do we do in terms of systemic evaluation? We now know the patient has HER2-positive, lymph node-involved, hormone receptor-negative disease, and I&rsquo;m already thinking of the neoadjuvant strategy. It seems quite appropriate for this patient. But I do want to look at her systemic staging studies because we know that this is a high-risk, highly proliferative and aggressive breast cancer, and it may have evidence of disease spreading. It&rsquo;s unlikely when a patient walks in, but I do consider doing laboratory evaluation to look at liver enzymes for the patient and then get a baseline systemic approach in terms of imaging, whether it&rsquo;s a CT [computed tomography] scan, PET [positron emission tomography] scan, or a combination of scans to take a look at liver, lung, and bones.

The prognosis for this patient these days is fabulous. I think if we look a little bit back in time, before we had a real understanding of the HER2-signaling pathwayand more specifically, drugs very specifically targeted for this pathway that are now part of standard care, Herceptin and Perjeta in this case&mdash;we&rsquo;ve changed what was previously a very poor prognostic cancer, where patients had a very aggressive disease course. We have now tailored and directed specific HER2 dual-targeted therapy as part of the treatment approach and elevated the cancer to one of the cancers that has the best prognostic outcome if that disease is sensitive to treatment.

Assessing a Case of Early-Stage HER2+ Breast Cancer

A multidisciplinary approach is key for our HER2-positive patients. Regarding the reason that a multidisciplinary approach is so key, I can think of all these cases that have come through our tumor board, which is really trying to guide what is going be the bird&rsquo;s-eye view of all the different modalities that are going to touch this patient during the course of her therapy now that we&rsquo;ve established the diagnosis of a HER2-positive, hormone receptor-negative breast cancer.

When I meet with these patients, I&rsquo;m already able to talk about potential downstaging with neoadjuvant treatment upfront so that patients may have an ability to forgo a mastectomy and undergo breast-conserving surgery. Sometimes, we consider genetic testing, and that may incorporate a need to think about bilateral mastectomies and reconstructions. Trying to get all those players in up front so that they are able to see the patient during the course of her therapy becomes quite important, so the patient has time to process all these different parameters.

I think it&rsquo;s also important for this patient to know that there&rsquo;s a high likelihood or consideration for radiation therapy to follow her surgery; what that looks like in her planning about her life pre-surgery or post-surgery; and how all these key integral pieces are affected by this diagnosis and how we are all part of her team. I think the hardest part is when a patient becomes only focused on neoadjuvant therapy. And then, when we move into the surgical realm and start discussing what the surgical possibilities can be, it&rsquo;s quite overwhelming for a patient to process all of that.

I think laying out all the players upfront in that multidisciplinary approach and evaluating things at the time of surgery is a very fluid, real-time treatment process. Sometimes things change. I always tell patients, sometimes the toxicity of the therapy just doesn&rsquo;t match with the patient. Sometimes we move surgery up earlier. Knowing all the particular components that will have an integral part in making sure we give her the best chance to have disease-free and overall survival is key in the multidisciplinary approach.

The surgeons are very upfront with identifying HER2-positive patients, and I think for the most part they immediately pick up the phone in my practice&rsquo;s community and run the patient by me. Sometimes, I&rsquo;d say more often than not, they send the HER2-positive patientwhether they&rsquo;ve communicated with me or not&mdash;to discuss the potential of neoadjuvant therapy. I think the benefit from HER2-targeted neoadjuvant therapy is phenomenal. Our surgeons are probably our greatest advocates for medical oncology because they see these patients at surgery and they see those surgical reports that show a complete remission of disease at the time of surgery with a high PCR [pathological complete response] rate. And so, I think they&rsquo;re believers as well. I think the challenges are, Are there patients who we don&rsquo;t need to think about a neoadjuvant strategy for? Occasionally, I send one back to them and I say, &ldquo;This patient just doesn&rsquo;t have enough volume of disease to make that a really good approach,&rdquo; for that particular patient.

Multidisciplinary Approach to HER2+ Breast Cancer

The treatment options for a patient who presents with a HER2-positive breast cancer really focus on the timing of surgery and the timing of adjuvant therapy. The guidelines really support an approach of chemotherapy given with HER2-targeted therapy, both in the adjuvant and the neoadjuvant setting. Those are all going to be features of her disease. I think the key component is really looking at the timing and the sequencing. For this patient, who as a 2-cm tumor and lymph node-positive disease, the best recommendation would be to approach neoadjuvant chemotherapy with dual HER2-targeted therapy followed by surgery.

Now, discussing the specific parameters of chemotherapy gives some options for patients. There can be an anthracycline-based regimen followed by a taxane, at which time the standard of using dual HER2-targeted therapy is concurrently with a weekly taxane.

I&rsquo;m much more of a fan of the taxane/platinum programs, so docetaxel/carboplatin/Herceptin [trastuzumab]/Perjeta [pertuzumab]. I think it&rsquo;s really well tolerated. The issue of cardiotoxicity is a little different between the regimens. They&rsquo;re very effective regimens, both of them. But I do think the risk of cardiotoxicity and symptomatic congestive heart failure is slightly higher in the anthracycline-based regimen. I also look at whether the patient has left-sided breast cancer or whether there&rsquo;s going to be a role of radiation therapy, and that certainly would dissuade me from the consideration of an anthracycline-based regimen. But largely I practice with a docetaxel/carboplatin, dual HER2-targeted neoadjuvant regimen.

When I talk to patients about treatment options, I do talk about how the standard was just single-agent HER2-targeted therapy with chemotherapy, and then we looked at the data that have evolved regarding the addition of pertuzumab to Herceptin in neoadjuvant therapy and what the advantages of that are to the patient.

We have a long discussion because the therapy can come with a few more adverse effects, but the advantages increase the chance that there&rsquo;s no disease at the time of surgery. We know from our meta-analysis that patients who have no disease at the time of surgery have the best disease-free and overall survival. For those patients, I really talk about Perjeta. It does have an increased risk of diarrhea for patients, and we talk about what that looks like currently with chemotherapy since some of the chemotherapy agents can also result in diarrhea and it&rsquo;s sometimes hard to distinguish. We talk about the prophylactic medications that we are going to try to get onboard if the patient does experience that toxicity. But I think with the advantages of the dual HER2-targeted therapy that has now become a standard of care for our HER2-positive patients in the neoadjuvant setting, we&rsquo;re going to really try hard to commit to that program. I have occasionally had to drop pertuzumab in a patient after dose modifying the chemotherapy. And then, I do revisit with that patient with pertuzumab in the adjuvant setting in the absence of chemotherapy.

HER2+ Early-Stage Breast Cancer: Neoadjuvant Strategies

The surgical outcomes for this patient are what we would have expected. When we see a patient receive neoadjuvant therapy with chemotherapy and the dual HER2-targeted agent, the expectation of a PCR [pathologic complete response] is upwards of 50%. Looking at this patient at the time of surgery, she had only a small residual burden of above 4 mm, but her lymph nodes were all negative and that certainly plays into the highest outcomes and prognostic features for the patienthaving lymph node-negative disease.

We&rsquo;re trying to incorporate how to make risk predictions for patients in terms of recurrence based on the presence or absence of residual disease after neoadjuvant therapy. If we look at this patient&rsquo;s 4-mm burden, she would likely fall into a residual cancer burden of 1 that has an excellent prognosis and really patterns after those patients who have a pathologic CR. I think that&rsquo;s an excellent finding for the patient, who has cleared her lymph nodes that were not only abnormal by imaging but also documented to have metastatic disease. I still think her prognosis is excellent based on the fact that we were able to eradicate the metastatic disease in the lymph nodes and have only this microscopic burden left in the breast.

Regarding the recommended adjuvant therapy for a HER2-positive patient who has undergone neoadjuvant therapy, the standard guidelines really look at Herceptin [trastuzumab], and that&rsquo;s where the data have been. When we look at the neoadjuvant trials, they gave a dual HER2-targeted therapy upfront, but at that time the trials completed the adjuvant component of their therapy post surgery with single-agent Herceptin. In looking at pertuzumab and the indications for pertuzumab in a high-risk patient in the adjuvant setting from the APHINITY data, I clearly think that this patient is a high-risk patient who had documented lymph node-positive disease, and I would recommend the addition of Perjeta, pertuzumab, to Herceptin in the adjuvant setting. That would typically be what I would talk to the patient about in the absence of any prohibitive toxicity.

When I look at the patient and try to figure out my adjuvant treatment strategies, I would say for anyone who I&rsquo;ve treated neoadjuvantly and who tolerated the dual HER2-targeted therapy, I have a tendency to continue that in the adjuvant setting. I do think if they had a lower risk cancermaybe just 2 cm nodes were noted to be negative&mdash;you could continue, and this would definitely be within the guidelines as well, just a Herceptin-based regimen. But for the most part, I think in patients who I treat with neoadjuvant dual HER2-targeted therapy and who are not facing an intolerance, I would continue that after surgery in the adjuvant fashion for the patient.

The dual HER2-targeted therapies have offered patients the best overall disease-free survival and overall survival, and we can look at both the neoadjuvant trials and really extrapolate that. In the case of the APHINITY trial as well, the addition of pertuzumab to HER2-targeted therapy was tested in the adjuvant setting, which I think is for a year of therapy. If I look at my practice preference of treating the patient both in the neoadjuvant and adjuvant setting, I think I&rsquo;m giving that patient the best chance for curability.

When we look at HER2-targeted therapy as a whole, we know that it&rsquo;s decreased the risk of recurrence in disease-free survival by 40%. And so, I would really want to offer that for patients. In the adjuvant trial, APHINITY, we know it had an absolute disease-free benefit for those patients and put their disease-free survival in the 90% or higher range. I really roll out all these treatment options for the patient to ensure that they&rsquo;re getting their best chance for curability.

Adjuvant Approaches to Treating HER2+ Breast Cancer

The role of radiation therapy in adjuvant and neoadjuvant settings has been on the increase. I think we&rsquo;ve really seen the value of radiation therapy in cases for which we previously did not even offer radiation therapy. This particular patient had no lymph node involvement. I think a patient with high-risk disease, in terms of having a HER2-positive biology, is definitely a patient who I would offer adjuvant radiation therapy to. I think when we look at the role of radiation in these patients, it clearly would decrease the risk of local regional recurrence. There&rsquo;s a suggestion that it may help improve disease-free survival, but it&rsquo;s really done with the goal of minimizing the local regional recurrence.

In this particular patient scenario, if we change her hormone receptor status and make her a hormone receptor-positive, HER2-positive patientnow known as a triple-positive breast cancer&mdash;there would be some different considerations. I would have expected a higher risk or amount of disease burden at the time of surgery. We know there are less pathologic complete responses in the HER2-positive, hormone receptor-positive patients. We also know that their risk of recurrence is a little bit higher.

I think the role for this patient would then be in the adjuvant setting, and I would definitely have added an anti-estrogen therapy for this patient. I think there was a trial that looked at adding it up front because we know that this disease has a signaling pathway that may bypass the benefits of some of the HER2-targeted therapies. They actually looked at adding adjuvant endocrine therapy up front in the neoadjuvant setting to see if blocking 2 different signaling pathways in these triple-positive tumors would result in better outcomes, and it did not.

An aromatase inhibitor is what I typically use in my HER2-positive patients in the adjuvant setting, and I would start that after surgery in combination with her dual HER2-targeted therapy. In the hormone receptor-positive, HER2-positive patients, I think there are some new data for extended HER2-targeted therapy with neratinib. I think the data clearly don&rsquo;t fit this particular patient because the neratinib study was not done in patients who had received prior pertuzumab. I always talk to my patients about how there is another therapy that has been approved. When we look at the subset analysis of that particular trial that tested neratinib, an oral HER2-targeted agent, following a year of the HER2-targeted therapy, at that time the trials were all Herceptin [trastuzumab]-based, so the standard wasn&rsquo;t dual HER2-targeted therapy. The patients did not get Herceptin and Perjeta [pertuzumab], so it&rsquo;s difficult to extrapolate.

The benefit was quite small, on the magnitude of 1% to 2%. The hormone receptor-positive subgroup suggested that they benefited from the extended HER2-targeted therapy following their year of Herceptin. I&rsquo;ve mentioned it to patients. I have not prescribed it to patients. I talk about the caveats. We don&rsquo;t know if there is benefit in a patient who has already received pertuzumab. And then, we do talk about the adverse effects of neratinib, which include a fairly substantial risk of diarrhea. When these patients are now a year from completing their therapy and are looking at another year of potential quality of life issues from toxicity with an unknown benefit, most aren&rsquo;t excited about going on to neratinib either.

This patient was a HER2-positive, hormone receptor-negative patient who was appropriate for neoadjuvant therapy and continued to receive and complete a year of adjuvant HER2-targeted therapy. Looking at what the future may hold for this patient population is challenging because the outcomes are so great now with the addition of HER2-targeted therapy. Even if we look at the APHINITY trial, where pertuzumab was given in the adjuvant setting completely, we&rsquo;re looking at survival and disease-free survival of 90% or more. It&rsquo;s hard to see how we&rsquo;re going to further affect that or increase that.

We do have some novel HER2-targeted agents and novel drug antibody conjugates that have made it into the adjuvant setting, and we&rsquo;re trying to stratify now which HER2-positive patient requires which chemotherapy and dual HER2-targeted therapy. There have been some trials in node-negative small tumors, whether we could just use a taxane and Herceptin-based regimen. They&rsquo;ve explored the role of potentially using T-DM1 or calcyon-targeted therapy in that population, which has less overall systemic toxicity for the patient. Trials are looking at elderly HER2-positive patients, and can we approach them differently depending on low-risk disease versus high-risk, HER2-positive disease.

I think we&rsquo;re now able to really focus on the subgroups of the HER2-positive patients. I think the biggest take-away is now trying to deescalate therapy. Does everybody need the one-size-fits all chemotherapy regimen, or can we start paring it down to be a single chemotherapy agent with dual HER2-targeted therapy or just monotherapy? Future strategies are looking at trying to strip some therapy recommendations away and tailor it to a node-negative, elderly patient with hormone receptor-positive disease.

HER2+ Early-Stage Breast Cancer: Perioperative Approaches

Assessing a Case of Early-Stage HER2+ Breast Cancer

Multidisciplinary Approach to HER2+ Breast Cancer

HER2+ Early-Stage Breast Cancer: Neoadjuvant Strategies

Adjuvant Approaches to Treating HER2+ Breast Cancer

Optimizing the Perioperative Management of Breast Cancer