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FAQ: Neo/adj Tx in EBC
Expert Answers to FAQ on Neo/Adjuvant Therapy in Early Breast Cancer

Released: February 07, 2023

Expiration: February 06, 2024

Joyce O'Shaughnessy
Joyce O'Shaughnessy, MD
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Key Takeaways
  • Patients with high-risk early breast cancer (EBC) can benefit from adjuvant abemaciclib regardless of Ki-67 score.
  • Olaparib may be preferred over abemaciclib in patients with BRCA-mutated hormone receptor–positive/HER2-negative EBC due to a demonstrated overall survival benefit.
  • Treatment de-escalation and proceeding to surgery may be considered for lower-risk patients with early triple-negative breast cancer who have a rapid exceptional response to the preoperative paclitaxel/carboplatin plus pembrolizumab portion of the KEYNOTE-522 regimen.

In this commentary adapted from a live satellite symposium at the 2022 San Antonio Breast Cancer Symposium (SABCS), program chair Joyce O’Shaughnessy, MD, answers audience questions and expands on panel discussion of the evolving role of biomarkers in guiding neoadjuvant and adjuvant therapy for early breast cancer (EBC).

How would you treat a patient with EBC who has 3/3 positive nodes, grade 2 disease, is T2, and has a Ki-67 score of 18%?
I would recommend adjuvant abemaciclib plus endocrine therapy for this patient. The FDA approval requires a Ki-67 score ≥20% to be eligible for adjuvant abemaciclib, but guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network do not, as long as the patient has other high-risk characteristics.

There can be quite a bit of variability in Ki-67 testing, even when conducted by expert pathologists. In my opinion, a Ki-67 score of 18% is close enough to 20% to justify recommending abemaciclib to this patient, given that she is otherwise at a high risk of recurrence. Furthermore, because she has 3/3 positive nodes, she quite likely would have a fourth positive node if more than 3 nodes had been removed.

It would not surprise me if the FDA reconsiders the high Ki-67 requirement for adjuvant abemaciclib. The registrational monarchE trial showed that although patients with lower Ki-67 scores had a better prognosis, the subgroups with high and low Ki-67 scores both showed invasive disease–free survival benefit with adjuvant abemaciclib. With longer follow-up, the delta is increasing between patients who received abemaciclib and those who did not.

What would you recommend for the following scenario?
A 58-year-old postmenopausal woman presented with a 6-cm right breast mass and a suspicious node. Her initial breast biopsy revealed invasive ductal carcinoma that is grade 2, hormone receptor (HR) positive, and HER2 negative with a Ki-67 score of 10%. Fine-needle aspiration of a palpable right node reveals adenocarcinoma of the breast, and testing is positive for a pathogenic BRCA2 mutation. She received neoadjuvant chemotherapy and underwent a bilateral mastectomy, with the right mastectomy specimen revealing a 5-cm mass with minimal chemotherapy effect and 2/15 positive nodes.

This patient would be eligible for enrollment on both the monarchE and OlympiA trials of adjuvant abemaciclib and olaparib, respectively. I would treat her with olaparib, which has demonstrated an overall survival benefit, rather than abemaciclib. As reported by Johnston and colleagues at SABCS 2022, monarchE has not shown a survival benefit for adjuvant abemaciclib, but the data remain immature.

I would not sequence abemaciclib after olaparib, no matter how high risk the patient is, because I would be concerned about doing harm without any potential of benefit. We do not know the characteristics of the residual disease that could persist after olaparib and whether this residual disease would respond to abemaciclib. Data from the setting of metastatic HR-positive breast cancer suggest that patients with germline BRCA mutations do not benefit as much from CDK4/6 inhibitor–based therapy.

Would you consider olaparib for a patient with HR-positive EBC who has 3/3 positive nodes and is high risk (ie, T3)?
I would consider olaparib in this situation and test the patient for BRCA mutations. The OlympiA trial required that patients with HR-positive disease be very high risk with ≥4 positive nodes, but in practice, patients may have more limited sentinel lymph node surgery, with or without targeted axillary dissection. Increasingly, surgeons are not doing full axillary dissection in patients with node-positive disease if the patient is planned for radiation therapy, as axillary radiation can be given instead. As I mentioned earlier, a patient with 3/3 positive nodes would be quite likely to have a fourth positive node if more nodes had been removed.

Would you consider treatment de-escalation for a 48-year-old woman who was diagnosed with T2N1 right triple-negative breast cancer and initiated paclitaxel, carboplatin, and pembrolizumab, who then had no palpable disease after her first cycle of therapy? An MRI after 12 weeks of therapy demonstrated a radiographic complete response (CR).
This is a great case. This patient had an incredible response despite having serious T2N1 disease. Should she continue the full KEYNOTE-522 regimen—which would involve sequencing to doxorubicin and cyclophosphamide (AC) and continuing pembrolizumab before surgery—or go immediately to surgery and then continue adjuvant pembrolizumab alone?

The question actually is: Will she have as excellent an outcome if she has a pathologic CR following the first half of the KEYNOTE-522 regimen as she would with a pathologic CR following receipt of the whole preoperative chemotherapy regimen from KEYNOTE-522? We are still building the evidence base to determine if how one achieves a pathologic CR matters—is a pathologic CR a pathologic CR no matter what preoperative therapy one receives to achieve this? For now, healthcare professionals must make their own calls, but I think the data are shaping up to support this hypothesis. For lower-risk patients who are exceptional responders like this one, I would de-escalate and go to surgery. If she had a pathologic CR, I would forgo AC chemotherapy and continue to adjuvant pembrolizumab alone. For higher-risk patients, I usually complete the full KEYNOTE-522 regimen of perioperative pembrolizumab and chemotherapy.

Do ESR1 mutations have clinical utility in practice?
Because ESR1 mutations are driven in part by exposure to endocrine therapy, especially aromatase inhibitor therapy, I look for these mutations in patients with metastatic disease rather than in those with EBC. In our clinic, we usually sequence all patients with metastatic disease in the first-line setting, obtaining circulating tumor DNA and next-generation sequencing of the metastatic biopsy.

Are ESR1 mutations actionable? We have seen benefit with fulvestrant compared with an aromatase inhibitor in this setting, and data now indicate considerable benefit with elacestrant in ESR1-mutant disease. When elacestrant receives FDA approval, I will consider this agent an excellent option for this setting.

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