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An Expert Tour of Recent Developments in Early-Stage Breast Cancer

Heather McArthur, MD, MPH
Program Director

Associate Professor
Department of Medicine
Medical Director, Breast Oncology
Samuel Oschin Comprehensive Cancer Center
Cedars-Sinai Medical Center
Los Angeles, California

Heather McArthur, MD, MPH: consultant/advisor/speaker: AstraZeneca, Bristol-Myers Squibb, Crown Bioscience, Daiichi Sankyo, Gilead Sciences, Immunomedics, Lilly, Merck, Pfizer, Puma Biotech, Seattle Genetics; researcher: Bristol-Myers Squibb, Merck.

View ClinicalThoughts from this Author

Released: August 4, 2022

Key Takeaways

  • The guidelines for perioperative treatment of high-risk early-stage breast cancer are still evolving.
  • For patients with wild-type BRCA, consider adjuvant abemaciclib plus endocrine therapy for hormone receptor–positive early-stage breast cancer and capecitabine for early-stage triple-negative breast cancer.
  • For patients with a germline BRCA mutation, consider adjuvant olaparib plus endocrine therapy or pembrolizumab in early-stage triple-negative breast cancer.

The treatment paradigm for early-stage breast cancer (EBC) has undergone rapid evolution during the past couple years. In this commentary, Heather McArthur, MD, MPH, shares key clinical takeaways on the latest developments in EBC from her live symposium at ASCO 2022 with Jennifer K. Litton, MD, and Rita Nanda, MD.

Updates in High-Risk Hormone ReceptorPositive and/or BRCA-Positive EBC

MonarchE: Adjuvant Abemaciclib Plus Endocrine Therapy
The CDK4/6 inhibitor abemaciclib was approved by the FDA in October 2021 as adjuvant treatment in combination with endocrine therapy (ET) for patients with hormone receptor (HR)–positive, HER2‑negative, node‑positive EBC at high risk of recurrence with a Ki-67 score ≥20%. This approval was based on the randomized phase III monarchE study of 2 years of standard ET with or without abemaciclib; this study also enrolled a cohort with ≥4 positive lymph nodes and Ki-67–low disease. The 3-year invasive disease-free survival (DFS) rate was 88.8% with abemaciclib plus ET vs 83.4% with ET, yielding a significant 5.4% difference (HR: 0.696; nominal P = .0001) with consistent benefit across subgroups. In this preliminary analysis, there was no overall survival (OS) benefit after 3 years with the addition of abemaciclib.

Of note, in the high-risk group, a high Ki-67 index was prognostic for worse invasive DFS but not predictive of benefit from abemaciclib. This is why ASCO and NCCN recommend abemaciclib for patients with ≥4 lymph nodes or 1-3 nodes plus grade 3 disease, a large primary tumor (≥5 cm), and/or Ki-67 ≥20%.

Abemaciclib: AE Management
Adverse events (AEs) were consistent with the established safety profile for abemaciclib. MonarchE reported a higher rate of diarrhea, pulmonary embolism, and interstitial lung disease with abemaciclib plus ET vs ET alone.

Patients receiving abemaciclib should start an antidiarrheal agent like loperamide, increase their fluid intake, and notify their care team at the first sign of diarrhea. Regarding neutropenia, complete blood count with differential should be monitored closely at the start of the first 4 cycles. Dose modifications can be used for managing both diarrhea and neutropenia.

OlympiA: Adjuvant Olaparib
Treating patients with EBC and germline BRCA mutations is an ongoing area of investigation. Earlier, the phase II NeoTALA study reported that neoadjuvant treatment with the PARP inhibitor talazoparib in HER2-negative, BRCA-mutated EBC was associated with a pathologic complete response (pCR) rate of nearly 50%, similar to standard chemotherapy.

More recently, the phase III OlympiA study compared adjuvant olaparib vs placebo in patients with germline BRCA1/2–mutated, HER2-negative disease that was either HR-positive EBC or early-stage triple-negative breast cancer (TNBC). At 36 months, the invasive DFS rate was 85.9% with olaparib vs 77.1% with placebo (HR: 0.58; P <.001). There was a small but significant OS improvement with olaparib (48-month OS rate: 89.8% vs 86.4%; HR: 0.68; P = .009).

Based on these results, the FDA approved adjuvant olaparib for adults with germline BRCA mutations and HER2-negative, high-risk EBC following (neo)adjuvant chemotherapy.

Olaparib: AE Management
Anemia is the most common AE with PARP inhibitors; 5.8% of olaparib-treated participants in OlympiA required red blood cell transfusions vs 0.9% treated with placebo. Anemia, neutropenia, and thrombocytopenia can be managed with dose modifications. Although 25% of participants had olaparib dose reduced and 9.9% discontinued due to AEs (vs 4.2% with placebo), there was no significant difference in global health quality between arms. Pneumonitis and secondary myelodysplastic syndromes and acute myeloid leukemia have been reported with olaparib, but these are rare.

Who Should Be Tested for BRCA1/2 Mutations?

There is an active debate around which patients with EBC should be tested for BRCA mutations. We know that all patients with metastatic breast cancer and all patients younger than 60 years of age with TNBC should be tested. At some point, guidelines may recommend that all patients with breast cancer be tested. For now, it is reasonable to perform BRCA testing in patients who could potentially be a candidate for the OlympiA trial in addition to those who meet NCCN guidelines.

Role of Immunotherapy for Early-Stage TNBC
TNBC accounts for 15% to 20% of all breast cancers and is a particularly immunogenic subtype. Compared with other breast cancer subtypes, TNBC is generally more responsive to PD-1/PD-L1 blockade with higher levels of tumor-infiltrating lymphocytes, higher PD-L1 expression, more genomic unstable tumors, and a higher tumor mutational burden. Immune checkpoint inhibitor monotherapy produced modest responses in metastatic TNBC (overall response rate [ORR]: ~25%); however, responses were more common in PD-L1–positive disease with high levels of tumor-infiltrating lymphocytes (ORR: ~40%).

Combination therapy shows greater activity in TNBC. In 2021, the FDA approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment for patients with high-risk early-stage TNBC followed by adjuvant pembrolizumab monotherapy. It is hoped that moving PD-1/PD-L1–targeted agents earlier in the treatment course might reduce the risk of recurrence.

The approval in early-stage TNBC was based on results from KEYNOTE-522, which enrolled patients with TNBC who had tumors 1-2 cm in diameter if there was nodal involvement or >2 cm regardless of nodal involvement. Patients with newly diagnosed T1cN1-2 or T2-4N0-2 TNBC were randomized to receive neoadjuvant chemotherapy with pembrolizumab or placebo. After surgery, pembrolizumab was continued as adjuvant monotherapy.

The pembrolizumab arm showed a 14% improvement in pCR rate (64.8% vs 51.2% in the placebo arm) and a higher 3-year event-free survival (EFS) rate (84.5% vs 76.8%). Those with a pCR had comparable 3-year EFS rates (~93%) with chemotherapy regardless of whether they received pembrolizumab or placebo. Those without a pCR had lower EFS rates compared with those with pCR, but the EFS rate was noticeably better with pembrolizumab vs placebo (67.4% vs 56.8%).

IMpassion031 is an ongoing phase III trial of perioperative treatment for stage II/III TNBC with tumors larger than 2 cm. All patients received nab-paclitaxel followed by doxorubicin/cyclophosphamide and surgery. Patients were randomized to neoadjuvant atezolizumab vs placebo followed by either adjuvant monotherapy with atezolizumab or observation. The pCR rate significantly improved in the atezolizumab arm (58% vs 41% in the placebo arm), and the benefit was consistent regardless of PD-L1 expression. We await EFS data.

GeparNUEVO is a relatively small, randomized phase II trial that compared neoadjuvant chemotherapy in combination with durvalumab vs placebo in 174 patients with untreated early-stage TNBC. After a median follow-up of approximately 3.5 years, durvalumab showed small but significant improvement in 3-year OS rates (95.2% vs 83.5%; HR: 0.24; P = .0108) in the context of a relatively modest improvement in 3-year pCR rates (53.4% vs 44.2%; P = .224).

Overall, these results with durvalumab are consistent with those reported for pembrolizumab in KEYNOTE‑522 and atezolizumab in IMpassion031. It is exciting to see the benefit from adding immunotherapy in the early-stage setting.

Managing irAEs in EBC
Immune-related AEs (irAEs) are common in EBC because patients have an immune system that is generally more intact than in the metastatic setting. Because irAEs can affect nearly any organ, healthcare professionals need to have a low threshold for identifying suspected irAEs. Most irAEs seen in EBC are mild to moderate, although severe, life-threatening toxicities are possible. Onset can vary, but most irAEs tend to occur during treatment, although irAEs can occur even several years after stopping therapy.

Early recognition and treatment are critical. Most irAEs are reversible with the exception of endocrine toxicities. In KEYNOTE-522, reported irAEs included infusion reactions in 18% of patients, hypothyroidism in 15%, severe skin reactions in 6%, and hyperthyroidism in 5%. Diabetes and adrenal insufficiency were seen at low levels (<3%), but these events are irreversible and important to identify prior to surgery.

Guidelines for grading and managing irAEs are available from ASCO, SITC, ESMO, and NCCN. Both the oncology care team and specialists need to be involved in irAE assessment and management, as oncologists may not be sufficiently familiar with toxicities outside of their area of specialty. Steroids are highly effective at managing most irAEs, but holding or discontinuing treatment may be required. Most patients can restart treatment once the irAE subsides. In the neoadjuvant setting, restarting treatment may be delayed until after surgery. Patients who have not achieved a pCR and have moved on to capecitabine or olaparib may experience worse irAEs. Some toxicities, such as colitis, can be managed effectively but then flare up again later.

Perioperative Therapy Considerations in EBC

Treatment Algorithm
The guidelines for perioperative treatment are still evolving with no consensus yet emerging. For adjuvant therapy in high-risk patients with wild-type BRCA, abemaciclib plus ET may be appropriate for those with HR-positive EBC and capecitabine for those with TNBC. If patients previously received immunotherapy (eg, as neoadjuvant treatment), they can continue the immunotherapy with adjuvant chemotherapy after surgery.

For patients who have a germline BRCA mutation, current optimal treatment might be olaparib plus ET. Another option might be abemaciclib, given the invasive DFS benefit seen in monarchE. Patients with early-stage TNBC could also receive the KEYNOTE-522 regimen of pembrolizumab added to neoadjuvant chemotherapy. For those with a BRCA mutation who do not achieve a pCR, olaparib may be added to the pembrolizumab. Lastly, combining radiation with concurrent pembrolizumab is another adjuvant option.

Role of Adjuvant Immunotherapy
Is there a role for adjuvant immunotherapy if patients have received neoadjuvant immunotherapy? In GeparNUEVO, durvalumab was given in only the neoadjuvant setting. In KEYNOTE-522, pembrolizumab was given before and after surgery. With the caveat that cross-trial comparisons are problematic, the long-term EFS curves were very similar between these studies. This raises the question of whether we should administer adjuvant immunotherapy after neoadjuvant immunotherapy given the toxicity risk. We may get answers from the ongoing phase III SWOG 1418 study (NCT02954874), which is randomizing patients with residual disease after neoadjuvant chemotherapy to pembrolizumab vs 1 year of observation, as well as the phase III IMpassion030 study (NCT03498716), which is evaluating atezolizumab plus adjuvant chemotherapy for 1 year in early-stage TNBC.

As mentioned earlier, the EFS rates in KEYNOTE-522 were comparable with pembrolizumab vs without pembrolizumab in patients who achieved a pCR. Could these patients have just received chemotherapy and skipped the pembrolizumab? Or, as in GeparNUEVO, could they receive a shorter course of just neoadjuvant immunotherapy? It is hoped that we will identify biomarkers to help determine which patients are most likely to achieve a pCR.

In patients who did not achieve a pCR in KEYNOTE-522, more than 10% still benefited from the addition of pembrolizumab to chemotherapy, but more than one third recurred within 3 years. This population still needs more effective therapy.

Optimal Chemotherapy Partner for Immunotherapy
There has been substantial debate over which chemotherapy partner is optimal, as not every patient with EBC needs platinum. Adjuvant capecitabine is often used for patients with residual disease and has a proven OS advantage. But should it be given concurrently with immunotherapy? In a study by Page and colleagues, the addition of pembrolizumab to either paclitaxel or capecitabine in metastatic TNBC showed that the capecitabine combination performed well, with a 43% ORR at 12 weeks, suggesting it might be safe and effective in earlier lines of therapy.

There has been much effort to develop anthracycline-free regimens, but anthracyclines still offer a huge benefit in patients with node-positive TNBC. For example, anthracycline regimens provided an approximately 11% improvement in invasive DFS vs cyclophosphamide, methotrexate, and 5-fluorouracil in the ABC trials.

Current clinical evidence can be confusing. In the TONIC study, anthracycline was beneficial when given prior to immunotherapy with nivolumab. Then, the I-SPY 2 study showed that pembrolizumab without an anthracycline performed just as well as doxorubicin, cyclophosphamide, and paclitaxel. Dose density is important, as dose-dense regimens provide superior OS. However, growth factors (eg, pegfilgrastim) must be given with dose-dense chemotherapy, and their effect on immunotherapy efficacy is unknown. It is hoped we will get some answers from the phase III GeparDouze study (NCT03281954), which is randomizing patients with TNBC to neoadjuvant anthracycline therapy every 2 or 3 weeks with immunotherapy vs without immunotherapy.

Your Thoughts?
Will you change your practice considering these new data? Answer the polling question and join the conversation by posting a comment in the discussion section.

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