Guidance for Canadian Breast Cancer Practice: National Consensus Recommendations for the Systemic Treatment of Patients with HER2+ Breast Cancer in Both the Early and Metastatic Setting
Abstract
:1. Introduction
2. Materials and Methods
2.1. Consensus Recommendation Process
2.2. Guiding Principles
3. Systemic Therapy in HER2+ Breast Cancer
3.1. Early Breast Cancer
Neoadjuvant Regimen * | Adjuvant Regimen | Primary Outcome | Secondary Outcomes | |
---|---|---|---|---|
NeoSphere [29,30] | DHP (Q3W × 4) DH (Q3W × 4) | FEC (Q3W × 3) | pCR: 45.8% vs. 29.0% | 5-year PFS: 86% vs. 81% (HR 0.69, 95% CI 0.34–1.40) 5-year DFS: 84% vs. 81% (HR 0.60, 95% CI 0.28–1.27) |
PEONY [31,32] | DHP (Q3W × 4) DH (Q3W × 4) | FEC (Q3W × 3) followed by HP (13 cycles) FEC (Q3W × 3) followed by H (13 cycles) | pCR: 39.3% vs. 21.8% (Δ = 17.5%, 95% CI 6.9–28.0%, p = 0.001) | 5-year EFS: 84.8% vs. 73.7% (HR 0.53, 95% CI 0.32–0.89) 5-year DFS: 86.0% vs. 75.0% (HR 0.52, 95% CI 0.30–0.88) 5-year OS: 93.9% vs. 90.0%(HR 0.53, 95% CI 0.23–1.19) |
BERENICE [33] | ddAC (Q2W × 4) followed by T (QW × 12) + HP (Q3W × 4) FEC (Q3W × 4) followed by DHP (Q3W × 4) | HP (Q3W × 13) | NYHA class III/IV heart failure (patients): 3 (1.5%) vs. 0 Confirmed LVEF decline †: 2 (1.0%) vs. 1 (0.5%) | 5-year EFS: 90.8% vs. 89.2% 4-year iDFs: 92.6% vs. 91.1% 5-year OS: 96.1% vs. 93.8% pCR: 61.8% vs. 60.7% |
TRYPHAENA [36,39] | FEC + HP (Q3W × 3) followed by DHP (Q3W × 3) FEC (Q3W × 3) followed by DHP (Q3W × 3) TCHP (Q3W x 6) | H (up to 1 year) | Symptomatic LVSD: 0 vs. 2 (2.7%) vs. 0 LVEF decline ‡: 4 (5.6%) vs. 4 (5.3%) vs. 3 (3.9%) | 3-year DFS: 87% vs. 88% vs. 90% 3-year PFS: 89% vs. 89% vs. 87% 3-year OS: 94% vs. 94% vs. 93% |
TRAIN-2 [37,38] | HP + FEC (Q3W × 3) followed by HP + TC (Q3W × 6) HP + TC (Q3W × 9) | N/A | pCR: 67% vs. 68% (Δ= −1.5%, 95% CI −11 to 8, p = 0.95) | 3-year EFS: 92.7% vs. 93.6% (HR 0.90, 95% CI 0.50–1.63) 3-year OS: 97.7% vs. 98.2% (HR 0.91, 95% CI 0.35–2.36) |
3.2. Metastatic Breast Cancer
Study Population | Key Outcomes (Intervention vs. Comparator Arm), HR (95% CI) | Key Safety Observations | |
---|---|---|---|
DESTINY-Breast01 [54] Phase 2 T-DXd | HER2+ unresectable or mBC with prior T-DM1 (N = 184) | Median PFS: 19.4 months (14.1–25.0) Median OS: 29.1 months (24.6–36.1) | Grade ≥3 TEAE occurred in 53.8% of patients Most common TEAEs GI or hematologic Drug-related ILD/pneumonitis in 15.8% |
NALA [60] Phase 3 Neratinib + capecitabine (+loperamide prophylaxis) vs. lapatinib + capecitabine | HER2+ mBC and ≥ 2 previous HER2-directed mBC therapies (N = 621) | PFS: 0.76 (0.63–0.93) OS: 0.88 (0.72–1.07) | Diarrhea, nausea, PPES, vomiting most common AEs of any grade overall More grade 3 diarrhea with neratinib No new cardiac safety concerns |
Subgroup with ≥3 previous HER2-targeted regimens: 30% | PFS: 0.71 (0.50–1.00) OS: 0.71 (0.50–1.02) | ||
NCT00078572 [61] Phase 3 Lapatinib + capecitabine vs. capecitabine alone | HER2+ locally advanced or mBC and progression after anthracycline, taxane, and H (N = 324) Prior H for mBC: 91% | PFS: 0.49 (0.34–0.71) OS: 0.92 (0.58–1.46) | Diarrhea, dyspepsia, rash, asymptomatic cardia events more common with lapatinib |
SOPHIA [62] Phase 3 Margetuximab vs. H, each in combination with chemotherapy (1 of capecitabine, eribulin, gemcitabine, or vinorelbine) | HER2+ mBC, ≥2 previous HER2-directed therapies, and 1–3 nonhormonal mBC therapy (N = 536) | PFS: 0.76 (0.59–0.98) OS: 0.89 (0.69–1.13) | Grade ≥3 AEs (≥5%): neutropenia, anemia (both groups); fatigue (margetuximab); febrile neutropenia (H) ↑IRRs with margetuximab; no increase in cardiac toxicity |
Subgroup with ≥3 previous mBC regimens: 34% | PFS: 0.72 (0.48–1.08) OS: 0.70 (0.47–1.05) |
3.3. Brain Metastases
3.4. Special Considerations
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Recommendations for Early Breast Cancer | REAL | ESMO | ASCO | |
---|---|---|---|---|
1 | cT1a and b, cN0 For patients with HER2+ early breast cancer cT1a and b (i.e., ≤1 cm) without evidence of nodal disease (cN0), the standard of care is timely surgery followed by adjuvant treatment depending on the pathologic staging of disease (see Recommendations 3–5). | Strong recommendation ●● | cT1 cN0 | |
2 | cT1c, cN0 For patients with HER2+ early breast cancer cT1c (i.e., >1 to ≤2 cm) without evidence of nodal disease (cN0), the standard of care is surgery followed by adjuvant treatment. However, due to current global practices, consideration can be given to neoadjuvant treatment followed by surgery and adjuvant treatment. | Strong recommendation ●● Strong consideration ○○ | NC No specific guideline for cT1c | For high-risk node-negative disease, pertuzumab may be used with trastuzumab |
3 | pT1, pN0 For patients with HER2+ early breast cancer with pT1 without evidence of nodal disease (pN0), the standard of care adjuvant systemic treatment is paclitaxel + trastuzumab for 12 weeks followed by trastuzumab monotherapy for 9 months. | Strong recommendation ●● | ||
4 | ≥pT2, pN0 Although neoadjuvant treatment is preferred, for those patients who are treated with upfront surgery and are then found to have ≥pT2 pN0 disease, the standard of care is adjuvant chemotherapy + trastuzumab. | Strong recommendation ●● | ||
5 | ≥cT2 or cN+ For patients with HER2+ early breast cancer with ≥cT2 or those with nodal disease (cN+), the standard of care is neoadjuvant therapy with trastuzumab + pertuzumab + chemotherapy. | Strong recommendation ●● | ||
6 | pN+ Although neoadjuvant treatment is preferred, for those patients who are treated with upfront surgery and are then found to have nodal disease in the pathological specimen (pN+), the standard of care is adjuvant chemotherapy + trastuzumab with consideration given to the addition of pertuzumab. | Strong consideration ○○ | Chemo + HP followed by HP to complete the year | |
7 | Pathologic complete response For patients with HER2+ early breast cancer in whom a pathologic complete response is determined in the surgical specimen after completion of neoadjuvant trastuzumab + pertuzumab + chemotherapy, the standard of care is trastuzumab for a total of 1 year. | Strong recommendation ●● | If cN0 at initial diagnosis If cN+ at initial diagnosis, then HP | |
8 | Residual invasive disease For patients with HER2+ early breast cancer in whom residual invasive disease is detected pathologically in the surgical specimen of the breast or axillary lymph nodes after completion of neoadjuvant trastuzumab + pertuzumab + chemotherapy, the standard of care is to treat with trastuzumab emtansine (T-DM1) for 14 cycles in the adjuvant setting. | Strong recommendation ●● | ||
9 | Hormone receptor-positive disease Although there is not a survival benefit, for patients with HER2+ HR+ and N+ disease who have completed (neo)adjuvant chemotherapy + trastuzumab, extended adjuvant treatment with neratinib for 1 year after completion of trastuzumab-based adjuvant therapy can be considered to decrease recurrence. | Moderate recommendation ● |
Recommendations for Metastatic Breast Cancer | Strength of Recommendation | ESMO | ASCO | |
---|---|---|---|---|
10 | Repeat biopsy When safe and feasible, repeat biopsy should be performed in all patients whose disease relapses on or after adjuvant treatment. | Strong recommendation ●● | ||
11 | 1L treatment late relapse For patients with de novo HER2+ (HR±) metastatic breast cancer who have not received prior HER2-directed therapy or chemotherapy for metastatic disease or with disease that relapses >6 months after completion of (neo)adjuvant chemotherapy + HER2-directed therapy, the standard of care is trastuzumab + pertuzumab + taxane chemotherapy followed by trastuzumab + pertuzumab +/− ET maintenance therapy. | Strong recommendation ●● | ||
12 | 1L treatment early relapse For patients with HER2-positive (HR±) metastatic breast cancer whose disease relapses ≤6 months after completion of (neo)adjuvant chemotherapy + HER2-directed therapy, the recommended treatment is as per the second-line recommendation (see Recommendation 13). | Strong recommendation ●● | (relapse ≤ 12 mos) | |
13 | 2L treatment For patients with HER2-positive metastatic breast cancer whose disease has progressed on first-line HER2-directed therapy, the standard of care is trastuzumab deruxtecan (T-DXd) in the absence of contraindications. | Strong recommendation ●● | ||
14 | 3L treatment For patients with HER2+ metastatic breast cancer whose disease has progressed after at least 2 HER2-directed therapies the recommendation for treatment is tucatinib + capecitabine + trastuzumab (can be considered earlier if brain metastasis is present). | Moderate recommendation ● | ||
15 | 4L and later treatment For patients with HER2+ metastatic breast cancer whose disease has progressed after at least 3 HER2-directed therapies, the recommendation based on evidence is to continue HER2-directed therapy. Options include T-DXd (preferred option, if not previously used); chemotherapy + trastuzumab or another monoclonal antibody; trastuzumab emtansine (T-DM1); neratinib +/- capecitabine; and lapatinib + capecitabine. | Moderate recommendation ● |
Recommendations for Brain Metastases | Strength of Recommendation | ESMO | ASCO | |
---|---|---|---|---|
16 | CNS screening For patients with HER2+ metastatic breast cancer who have symptoms suggestive of CNS metastases, appropriate diagnostic investigations for CNS metastases are essential. | Strong recommendation ●● REAL Alliance expert opinion ○ | If detection of CNS metastases will alter the choice of systemic therapy | |
For patients with HER2+ metastatic breast cancer, screening for CNS metastases should be considered in asymptomatic patients at baseline in the metastatic setting and at disease progression. | ||||
17 | Multidisciplinary care For patients with a history of HER2+ metastatic breast cancer who are diagnosed with brain metastases, multidisciplinary care with representation from radiology, radiation oncology, neurosurgery, medical oncology, and supportive care is the standard of care, with the multidisciplinary team providing recommendations on sequencing of local and systemic therapies. | REAL Alliance expert opinion ○ | NC | NC |
18 | Characteristics of CNS disease at screening For patients with a history of HER2+ metastatic breast cancer but without other extracranial systemic disease who present with oligometastatic brain disease amenable to local therapy, there is insufficient evidence to make a recommendation for a change in systemic therapy. Multidisciplinary care is the standard of care, and the multidisciplinary team is to make recommendations on sequencing of local and systemic therapies in such patients. | REAL Alliance expert opinion ○ | NC | NC |
19 | Characteristics of CNS disease at screening For patients with a history of HER2+ metastatic disease who present with asymptomatic, low volume, newly diagnosed brain metastases, treatment should be discussed by MDT incorporating patient values with treatment options including initial HER2-directed systemic therapy versus upfront local therapy. | REAL Alliance expert opinion ○ | NC | NC |
20 | Characteristics of CNS disease at screening For patients with a history of HER2+ metastatic disease who present with symptomatic, newly diagnosed brain metastases, upfront stereotactic radiosurgery is a reasonable approach when technically feasible (and often preferred over whole brain radiotherapy). | REAL Alliance expert opinion ○ | NC | NC |
21 | Characteristics of CNS disease at screening For patients with HER2+ metastatic breast cancer with parenchymal CNS disease, the decision to offer systemic therapy prior to local therapies should be individualized for each patient and ideally discussed at multi-disciplinary rounds. Key considerations include tumour burden and clinical symptoms. A multidisciplinary approach should be conducted to confirm if and when systemic therapy should be held during local CNS therapy to reduce the risk of toxicities and tumour necrosis. | REAL Alliance expert opinion ○ | NC | NC |
22 | 1L treatment stable brain metastases For patients with HER+ metastatic breast cancer with active or progressive systemic disease in the presence of treated brain metastases, the standard of care in the first line setting is trastuzumab + pertuzumab + taxane. | Strong recommendation ●● | ||
23 | 2L treatment stable brain metastases For patients with HER2+ metastatic breast cancer with stable brain metastases whose disease has progressed on first line therapy, the standard of care options are trastuzumab deruxtecan (T-DXd [preferred]), or tucatinib + capecitabine + trastuzumab. | Strong recommendation ●● | ||
24 | 2L treatment active brain metastases For patients with HER2+ metastatic breast cancer and asymptomatic active (i.e., untreated) or stable brain metastases where local therapy is not indicated and whose disease has progressed on first-line therapy, options include tucatinib + capecitabine + trastuzumab or T-DXd. Such cases should be reviewed by the multidisciplinary team to determine sequencing of local and systemic therapies. | Strong recommendation ●● | ||
25 | 3L treatment For patients with HER2+ metastatic breast cancer and active brain metastases whose disease has progressed on second-line systemic therapy, the standard of care is tucatinib + capecitabine + trastuzumab (preferred if not used in second line) or T-DXd (preferred if not used in second line or if there are signs of extensive systemic disease) | Strong recommendation ●● | NC |
Antibody–Drug Conjugate | Trastuzumab Deruxtecan [83] | Trastuzumab Emtansine [84] |
---|---|---|
Half life | 5.6 days | 3.1 to 4.5 days |
Recommendations for Other Areas of Interest | Strength of Recommendation | ESMO | ASCO | |
---|---|---|---|---|
26 | Drug holiday In patients with HER2+ metastatic breast cancer, a drug holiday can be considered in cases where there is stable disease based on imaging. | REAL Alliance expert opinion ○ | NC | NC |
27 | Multidisciplinary care In patients with HER2+ de novo metastatic breast cancer, who have a clinical complete response in the metastatic sites from chemotherapy + HER2-directed therapy and whose PET scan is negative, but who have breast-only residual disease, surgery can be considered at the site of the primary tumour to obtain no evidence of disease. | REAL Alliance expert opinion ○ | NC | NC |
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Manna, M.; Gelmon, K.A.; Boileau, J.-F.; Brezden-Masley, C.; Cao, J.Q.; Jerzak, K.J.; Prakash, I.; Sehdev, S.; Simmons, C.; Bouganim, N.; et al. Guidance for Canadian Breast Cancer Practice: National Consensus Recommendations for the Systemic Treatment of Patients with HER2+ Breast Cancer in Both the Early and Metastatic Setting. Curr. Oncol. 2024, 31, 6536-6567. https://doi.org/10.3390/curroncol31110484
Manna M, Gelmon KA, Boileau J-F, Brezden-Masley C, Cao JQ, Jerzak KJ, Prakash I, Sehdev S, Simmons C, Bouganim N, et al. Guidance for Canadian Breast Cancer Practice: National Consensus Recommendations for the Systemic Treatment of Patients with HER2+ Breast Cancer in Both the Early and Metastatic Setting. Current Oncology. 2024; 31(11):6536-6567. https://doi.org/10.3390/curroncol31110484
Chicago/Turabian StyleManna, Mita, Karen A. Gelmon, Jean-François Boileau, Christine Brezden-Masley, Jeffrey Q. Cao, Katarzyna J. Jerzak, Ipshita Prakash, Sandeep Sehdev, Christine Simmons, Nathaniel Bouganim, and et al. 2024. "Guidance for Canadian Breast Cancer Practice: National Consensus Recommendations for the Systemic Treatment of Patients with HER2+ Breast Cancer in Both the Early and Metastatic Setting" Current Oncology 31, no. 11: 6536-6567. https://doi.org/10.3390/curroncol31110484