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The Evolving Treatment of Early Breast Cancer: Expert Answers to FAQs

Released: July 25, 2023

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Key Takeaways
  • Assuming FDA approval of adjuvant ribociclib based on NATALEE, I would recommend this therapy to patients with HR-positive/HER2-negative early breast cancer (EBC) that is high risk and node negative or lower risk and node positive, for whom adjuvant abemaciclib is not indicated.
  • I prioritize adjuvant treatment with olaparib over adjuvant abemaciclib for patients with high-risk, germline BRCA2–mutated HR-positive/HER2-negative EBC.
  • In my practice, given the promising pCR results in the NEOPACT trial with preoperative docetaxel, carboplatin, and pembrolizumab, a patient with stage II triple-negative breast cancer (TNBC) who has an imaging complete response with the first half of the KEYNOTE-522 regimen of pembrolizumab plus paclitaxel/carboplatin can proceed to surgery, with the goal of de-escalating therapy and avoiding the anthracycline if she has a pCR.

In this commentary, Joyce O’Shaughnessy, MD, answers healthcare professional (HCP) questions on current dilemmas in the treatment of early breast cancer (EBC). The questions below were submitted by an audience of HCPs during an educational symposium on EBC.

How would you use ribociclib if the FDA approves a new adjuvant indication based on the NATALEE data?

This boils down to deciding between adjuvant treatment with ribociclib vs abemaciclib, the first CDK4/6 inhibitor approved in this setting. When faced with this decision, I would have a discussion with the patient about the available data and differences in therapy duration, efficacy, and safety.

Both CDK4/6 inhibitors significantly prolonged invasive disease–free survival in phase III trials. We already have 4-year follow-up data for abemaciclib in monarchE, which reported a 4-year invasive disease–free survival absolute benefit of 6.4% after all patients had come off study and 82% had completed their intended therapy. Our follow-up is shorter for NATALEE at around 34 months, and it will be important to see the long-term follow-up when more patients have completed ribociclib therapy.

Regarding therapy duration, adjuvant abemaciclib is given for 2 years, and adjuvant ribociclib is given for 3 years. This is very important because these higher-risk patients have generally had chemotherapy and then need to contend with the toxicities related to CDK4/6 inhibition for 2-3 more years plus those related to adjuvant endocrine therapy.

CDK4/6 inhibitors are expensive. We have to be mindful of the financial cost, which could exacerbate disparities in care between patients who cannot afford a long duration of therapy.

I would continue to recommend abemaciclib to patients who meet the monarchE eligibility criteria for high-risk disease unless the patient has a history of significant gastrointestinal comorbidities. With the current shorter follow-up on NATALEE, I would offer ribociclib to patients with high-risk, node-negative disease and to a subset of those with lower-risk disease with 1-3 positive nodes for whom abemaciclib is not indicated, as well as to the rare patients who cannot tolerate abemaciclib, even with dose reduction. These recommendations could change with longer follow-up of the NATALEE trial if the absolute improvement in invasive disease–free survival with ribociclib continues to grow larger as it has done in the monarchE trial.

How would you treat a postmenopausal woman with germline BRCA2–mutated, high-risk, hormone receptor (HR)–positive EBC who received neoadjuvant chemotherapy and underwent surgery but still has 4 positive nodes?
This is an uncommon scenario, given the relative rarity of BRCA2 mutations in HR-positive disease. Given the choice between adjuvant abemaciclib or olaparib, I would recommend olaparib because this agent significantly improved overall survival in patients with BRCA-mutated, high-risk EBC on the OlympiA trial. The survival data are still immature for abemaciclib in monarchE.

Although we currently do not have data demonstrating the effectiveness of abemaciclib following treatment with olaparib, I would consider sequencing abemaciclib after olaparib in my patients with highest-risk, node-positive, germline BRCA2–mutated HR-positive disease. monarchE enrolled patients with up to 16 months between the time of surgery and randomization. This means a patient still could potentially be eligible for adjuvant abemaciclib after completing 1 year of adjuvant olaparib.

There is some concern that CDK4/6 inhibitors may be less effective in germline BRCA2–mutated EBC, as has been reported in germline BRCA2–mutated metastatic disease. This reduced efficacy may be due to loss of the RB1 gene when BRCA2 is deleted, as these genes are in close proximity on chromosome 13. When a germline BRCA2–mutated cancer with a loss of 1 copy of RB1 is put under the selective pressure of CDK4/6 inhibition, the cancer can develop somatic loss of the remaining RB1 allele, thereby leading to CDK4/6 inhibitor resistance.

Is there a clinical role for monitoring circulating tumor DNA (ctDNA) in patients with high-risk EBC?
I do not recommend ctDNA monitoring in practice at this time. We currently lack data on whether intervening based on the presence of ctDNA will make a difference in improving disease-free or overall survival, and monitoring could lead to unnecessary scans, anxiety, and uncertainty about what to do with the information.

That said, the role of ctDNA monitoring is a very important research tool. Multiple studies show that patients with EBC positive for ctDNA are at a very high risk of recurrence, so we know that ctDNA is a poor prognostic sign.

If you had a patient with T2, clinically node-negative triple-negative breast cancer (TNBC) who received the first half of the KEYNOTE-522 regimen and had a radiographic complete response on MRI, would you go directly to surgery, or would you complete the regimen and then go to surgery?
I would consider going directly to surgery for a patient with stage II TNBC based on data from the single-arm phase II NeoPACT trial. NeoPACT reported a high pathologic complete response rate of 58% in patients with stage I-III TNBC who received neoadjuvant pembrolizumab plus carboplatin and docetaxel.

It would be an in-depth discussion with the patient because hopefully she would be willing to receive adjuvant AC (doxorubicin and cyclophosphamide) if she has pathologic residual disease. We will gain important insights on the safety of chemotherapy de-escalation in the context of preoperative pembrolizumab from the phase III SCARLET (SWOG S2212) trial, which is comparing the KEYNOTE-522 regimen to the shorter, anthracycline-free NeoPACT regimen in patients with early TNBC.

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