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Community Practice Connections™: Optimizing Outcomes in HER2-Positive Breast Cancer: Emerging Evidence and Practical Strategies in Early-Stage Treatment Settings PER Pulse™ Recap

PER Pulse Recap

PER Pulse™ Recap


1 of 3
PER Pulse™ Recap

HER2: Biology and Strategies for Optimal Assessment

The 34th Annual Miami Breast Cancer Conference®, held March 9-12, 2017, communicated state-of-the-art approaches for the management of patients with breast cancer, as well as emerging therapeutic paradigms. This first of 3 PER Pulse™ Recaps from the conference focuses on the biology of HER2+ breast cancer and strategies for optimal patient assessment.

In approximately 20% of primary breast cancers, there is amplification and/or overexpression of the human epidermal growth factor receptor 2 (HER2) gene.1 According to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations, HER2 status should be established for all patients with primary invasive breast cancer.1 This testing helps to guide therapeutic direction, and it is imperative to have an accurate assessment in order to optimize patient outcomes.

Although most HER2 tests are definitive, the possibility of equivocal testing does exist. Common testing techniques include assessment of immunohistochemistry (IHC) score or in situ hybridization (ISH). An initial equivocal test should be followed by reflex testing on the same specimen using the alternative test, or an alternative specimen if the pathologist has concerns about the initially tested specimen.1

The NSABP B-47 study is currently assessing patients who have node-positive or high-risk, node-negative breast cancer that has a HER2 status of 1+ or 2+ by IHC, but not amplified by fluorescence in situ hybridization (FISH).2 It is designed to test the hypothesis that patients who are HER2-negative may benefit from adjuvant trastuzumab, as suggested by the NSABP B-31 study.3

Of note, ASCO guidelines pertaining to the use of biomarkers to guide decisions on adjuvant therapy for women with early-stage, invasive breast cancer have been published recently.4 For patients with known HER2+ breast cancer, the guidelines recommend that clinicians not use several reviewed assays.4

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 34th Annual Miami Breast Cancer Conference®, including downloadable slides from the meeting.

References

  1. Wolff AC, Hammond ME, Jicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3397-4013.
  2. ClinicalTrials.gov. Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer (NCT01275677). https://clinicaltrials.gov/show/NCT01275677. Accessed May 1, 2017.
  3. Pogue-Geile KL, Kim C, Jeong J-H, et al. Predicting degree of benefit from adjuvant trastuzumab in NSABP trial B-31. J Natl Cancer Inst. 2013;105(23):1782-1788.
  4. Harris LN, Ismaila N, McShane LM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(10):1134-1150.

2 of 3
PER Pulse™ Recap

Assessing Long-Term Outcomes and the Need for More Effective Adjuvant Approaches to Early-Stage HER2+ Breast Cancer

The 34th Annual Miami Breast Cancer Conference®, held March 9-12, 2017, communicated state-of-the-art approaches for the management of patients with breast cancer, as well as emerging therapeutic paradigms. This second of 3 PER Pulse™ Recaps from the conference focuses on current and emerging clinical trial data pertaining to adjuvant therapy for patients with early-stage, HER2+ breast cancer.

Several landmark trials have laid the foundation for the current adjuvant therapy standard of chemotherapy plus 12 months of trastuzumab in patients with early-stage, HER2+ breast cancer. These include HERA, NSABP B-31, NCCTG N9831, and BCIRG 006.1-4

Strategies to improve adjuvant therapy‒associated outcomes for patients with early-stage, HER2+ breast cancer have recently undergone exploration, assessing potential modifications of the standard treatment regimen.5 Although many patients with HER2+ breast cancer have seen great improvement with the incorporation of trastuzumab, not all patients do well, either due to resistance to treatment or side effects with standard approaches.6

The combination of adding trastuzumab to the adjuvant nonanthracycline regimen of docetaxel plus cyclophosphamide for patients with early-stage, HER2-amplified breast cancer has been assessed in a single-group, open-label, phase II study. In this study, 2-year overall survival (OS) was noted to be 99.5%, and 2-year disease-free survival (DFS) was 97.8% for patients with TOP2A-amplified disease.7 The 2-year OS was 98.8% and the 2-year DFS was 97.9% for patients with TOP2A-nonamplified disease. The authors concluded that a 4-cycle treatment regimen of docetaxel and cyclophosphamide with trastuzumab may be an adjuvant option for women with lower-risk, early-stage, HER2-amplified breast cancer.7  

The BETH study8 was a randomized phase III study that assessed the influence of the addition of bevacizumab to adjuvant chemotherapy. The study showed that bevacizumab did not improve invasive DFS or OS in patients with high-risk, HER2+ breast cancer.8 Other studies, such as ALTTO, ExteNET, APHINITY, and TEACH, have assessed different combinations in the adjuvant setting.9-12

In the adjuvant setting, the use of lapatinib as monotherapy or in combination with trastuzumab has been assessed in both the ALTTO and TEACH trials.9,10 The ExteNET study11 assessed the use of neratinib after a year of adjuvant trastuzumab. Recent data suggest that, particularly for patients with estrogen receptor‒positive cancer, there is a benefit to the addition of neratinib for an additional year.11,13 There is approximately a 5.5% difference in favor of adding neratinib. Gastrointestinal side effects are common, particularly diarrhea. Most recently, the APHINITY study,12 which assessed the addition of pertuzumab to trastuzumab and chemotherapy in the adjuvant setting for early-stage, HER2+ breast cancer, has been reported to have met its primary endpoint of DFS.

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 34th Annual Miami Breast Cancer Conference®, including downloadable slides from the meeting.

References

  1. Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021-1028.
  2. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32: 3744-3752.
  3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.
  4. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365: 1273-1283.
  5. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14(8):741-748.
  6. Joensuu H. Escalating and de-escalating treatment in HER2-positive early breast cancer. Cancer Treat Rev. 2017;52:1-11.
  7. Jones SE, Collea R, Paul D, et al. Aduvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013;14(11):1121-1128.
  8. Slamon DL, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer. Presented at: the 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio,TX. Abstract S1-03.
  9. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34(10):1034-1042.
  10. Goss PE, Smith IE, O’Shaughnessy J, et al. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(1):88-96.
  11. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377.
  12. The ASCO Post. Phase III APHINITY Study: Adjuvant Pertuzumab/Trastuzumab/Chemotherapy Increased Invasive Disease–Free Survival in HER2-Positive Breast Cancer. http://www.ascopost.com/News/49404. Accessed May 4, 2017.
  13. Loibl S, Gianni L. HER2-positive breast cancer [published online December 6, 2016]. Lancet. 2016. DOI: http://dx.doi.org/10.1016/S0140-6736(16)32417-5.

3 of 3
PER Pulse™ Recap

Neoadjuvant Strategies for Patients with HER2+ Breast Cancer

The 34th Annual Miami Breast Cancer Conference®, held March 9-12, 2017, communicated state-of-the-art approaches for the management of patients with breast cancer, as well as emerging therapeutic paradigms. This third of 3 PER Pulse™ Recaps from the conference focuses on neoadjuvant strategies for patients with HER2+ breast cancer, with a review of clinical evidence.

When considering the use of neoadjuvant therapy for patients with HER2+ breast cancer, it is important to weigh the advantages and disadvantages of adjuvant versus neoadjuvant approaches. Accurate staging is imperative. The neoadjuvant approach may improve the rates of adequate surgical resection, particularly in breast-conserving surgery for patients who are stage 2 or higher.1 Clinical investigation has shown that pathologic complete response (pCR) at surgery has an association with improvements in disease-free survival (DFS) and overall survival (OS).2

Several other studies have assessed the HER2 dual blockade role with lapatinib and trastuzumab versus trastuzumab alone in the neoadjuvant setting for treatment of HER2+ breast cancer, including NeoALTTO, CALGB 40601, NSABP-B41, EORTC 10054, TRIO-US B07, and CHER-LOB.3-8 A meta-analysis of these 6 studies found that dual blockade with lapatinib and trastuzumab plus chemotherapy is active only in HER2+, hormone receptor‒negative (HR-negative) cancer treated with taxane monochemotherapy.9

The NeoSphere study10 assessed the potential of dual HER2 blockade with pertuzumab and trastuzumab. In this study, patients were randomized 1:1:1:1 to receive 1 of 4 different preoperative regimens for 12 weeks: docetaxel plus trastuzumab; docetaxel plus trastuzumab plus pertuzumab; trastuzumab plus pertuzumab; or docetaxel plus pertuzumab. Patients in the group that received docetaxel plus trastuzumab plus pertuzumab had a significantly greater rate of pCR than patients who received trastuzumab plus docetaxel (P=.0141).10 At 5-year follow-up of the NeoSphere study, the addition of pertuzumab to trastuzumab plus docetaxel suggested benefit with respect to progression-free survival and DFS.11

The TRYPHAENA study12 assessed the combination of pertuzumab with 6 cycles of different neoadjuvant chemotherapy regimens for patients with early and advanced HER2+ breast cancer.  In arm A, patients received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) plus trastuzumab plus pertuzumab ×3 followed by docetaxel plus trastuzumab plus pertuzumab ×3. In arm B, patients received FEC ×3 followed by docetaxel plus trastuzumab plus pertuzumab ×3. In arm C, patients received docetaxel plus carboplatin plus trastuzumab (TCH) plus pertuzumab ×6. Pathologic complete response rates were comparable, with 61.6% for arm A, 57.3% for arm B, and 66.2% for arm C. Patients were noted to have a low rate of symptomatic left ventricular systolic dysfunction with anthracycline combinations.12

Many agents are known to augment the effectiveness of antibody-based therapy and are also being assessed. The I-SPY 2 platform trial was designed to assess several treatment regimens in combination with standard neoadjuvant chemotherapy for high-risk, clinical stage II or III breast cancer, in order to assess the effect on rate of pCR.13,14 As a part of this study, neratinib was evaluated versus control for 10 biomarker signatures. Neratinib attained a prespecified efficacy threshold with regard to patients with HER2+, HR-negative disease. For patients with HER2+, HR-negative cancer, the mean estimated pCR rate was 56% for the group treated with neratinib compared with 33% for controls.14

For additional commentary about these topics and others, visit www.gotoper.com to access more resources from the 34th Annual Miami Breast Cancer Conference®, including downloadable slides from the meeting.

References

  1. Tripathy D. Using neoadjuvant therapy for breast cancer in clinical practice: when and how? Breast Cancer Res Treat. 2012;132(3):775-777.
  2. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.
  3. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379(9816): 633-640.
  4. Carey LA, Berry DA, Cirrincione CT, et al. Molecular heterogeneity and response to neoadjuvant human epidermal growth factor receptor 2 targeting in CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab with or without lapatinib. J Clin Oncol. 2016;34(6):542-549.
  5. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(12):1183-1192.
  6. Bonnefoi H, Jacot W, Saghatchian M, et al. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study. Ann Oncol. 2015;26(2):325-332.
  7. Hurvitz S, Miller J, Dichmann R, et al. Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07). Cancer Res. 2013;73(abstr S1-02).
  8. Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: results of the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30(16):1989-1995.
  9. Clavarezza M, Puntoni M, Gennari A, et al. Dual block with lapatinib and trastuzumab versus single-agent trastuzumab combined with chemotherapy as neoadjuvant treatment of HER2-positive breast cancer: a meta-analysis of randomized trials. Clin Cancer Res. 2016;22(18):4594-4603.
  10. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.
  11. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791-800.
  12. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013; 24:2278-2284.
  13. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1):23-24.
  14. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375(1):11-22.




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