ResourcesPER Pulse™ Recap
Three PER Pulse™ Recaps presenting key topics from the 32nd Annual Miami Breast Cancer Conference®, which was held on February 26 - March 1, 2015.
PER Pulse™ Recap
Medical Writer: Kim Farina, PhD
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PER Pulse™ Recap
32nd Annual Miami Breast Cancer Conference®
The multidisciplinary Miami Breast Cancer Conference® has been bringing together surgical, medical, and radiation oncologists for 32 years, with the aim of fostering awareness of the state-of-the-art treatments in each therapeutic area, and encouraging cross-team cooperation in the clinic. This first of 3 PER Pulse™ Recaps that is focused on the 32nd Annual Miami Breast Cancer Conference® examines the value of anti-HER2 therapy for patients with small HER2-positive tumors of the breast, as discussed by Dr. William Gradishar.
Dr. Gradishar reviewed the data related to the potential risks/benefits of using anti-HER2 therapy for patients with small breast tumors (<1 cm), for which existing evidence is uncertain and randomized clinical trial data are not available.
Potential benefits of anti-HER2 therapy for breast tumors less than 1 cm in size should be evaluated in the context of available outcomes data. Variable risk of recurrence rates have been observed among patients with HER2-positive, T1a,bN0M0 breast tumors who have not received treatment, according to a number of registry data sets (77%-99% 5-year relapse-free survival [RFS], disease-free survival [DFS], or distant-relapse-free survival).1-3 Data from a prospective cohort study within the National Comprehensive Cancer Network (NCCN) Database indicate 5-year relapse rates for patients with untreated T1a tumors of 2% to 7% and for untreated T1b tumors of 4% to 10%.4
Experts feel that there is a potential benefit to giving anti-HER2 therapy to patients with small breast tumors. Current NCCN guidelines for HER2-positive disease recommend5:
- Tumors ≤1 cm: Consider adjuvant trastuzumab (category 2b)
- Tumors >1 cm, pN0 or pN1mi: Offer adjuvant trastuzumab (category 1 evidence)
Results from a meta-analysis of randomized adjuvant trastuzumab trials (FinHER, PACS-04, NSABP B31, N9831, and HERA) support the use of trastuzumab for tumors 2 cm or less, regardless of hormone receptor status.6 However, application of these data to tumors less than 1 cm is limited by the fact that a very small number of patients within these trials were T1a or T1b; nearly all had T1c disease and positive axillary lymph nodes. In a phase II, single-arm trial of 3 months of paclitaxel/trastuzumab followed by 9-months of trastuzumab monotherapy (N = 406), 99% 3-year DFS was observed for patients with HER2-positive breast tumors 3 cm or less in size (T1a, 19%; T1b, 31%; T1c 42%; T2, 9%).7 Notably, very low rates of cardiac problems were reported in this trial (symptomatic congestive heart failure, <1%; asymptomatic decline in left ventricular ejection fraction, 3%). Looking forward, enrollment is under way for the phase II ATEMPT trial, which will randomize patients with stage 1 disease to trastuzumab-DM1 versus paclitaxel/trastuzumab followed by trastuzumab.8
In conclusion, Dr. Gradishar noted the variable outcomes among patients with small, HER2-positive tumors across data sets, with some populations experiencing significant risk of recurrence. He emphasized the need to individualize treatment decisions and commented on the limited data available for T1a tumors. Based on available data, he would consider discussing HER2-directed therapy for most patients with T1b or greater disease.
- Gonzales-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009;27:5700-5706.
- Curigliano G, Viale G, Bagnardi V, et al. Clinical relevance of HER2 overexpression/amplification in patients with small tumor size and node-negative breast cancer. J Clin Oncol. 2009;27:5693-5699.
- Fehrenbacher L, Shiraz P, Sattavat M, et al. T1abN0M0 HER2+ invasive breast cancer recurrence: population-based cohort of 17,000+ consecutive breast cancers 2000-2006 at Kaiser Permanente Northern California (KPNC). J Clin Oncol. 2011;29:(suppl; abstr 551).
- Vaz-Luis I, Ottesen RA, Hughes ME, et al. Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study. J Clin Oncol. 2014;32:2142-2150.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2015. March 11, 2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 19, 2015.
- O'Sullivan CCM, Bradbury I, De Azambuja E, et al. Efficacy of adjuvant trastuzumab (T) compared with no T for patients (pts) with HER2-positive breast cancer and tumors ≤2cm: a meta-analysis of the randomized trastuzumab trials. J Clin Oncol. 2014;32:(suppl 5s; abstr 508).
- Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015;372:134-141.
Clinicaltrials.gov website. T-DM1 vs Paclitaxel/Trastuzumab for Breast (ATEMPT Trial). ClinicalTrials.gov Identifier: NCT01853748.
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PER Pulse™ Recap
32nd Annual Miami Breast Cancer Conference®
Adjuvant Endocrine Therapy for Premenopausal Women With HR-Positive Breast Cancer
The multidisciplinary Miami Breast Cancer Conference® has been bringing together surgical, medical, and radiation oncologists for 32 years, with the aim of fostering awareness of the state-of-the-art treatments in each therapeutic area and encouraging cross-team cooperation in the clinic. This second of 3 PER Pulse™ Recaps that is focused on the 32nd Annual Miami Breast Cancer Conference® examines adjuvant endocrine therapy for premenopausal women with hormone receptor (HR)-positive breast cancer, as discussed by Dr. Hope Rugo.
After reviewing established and emerging data on adjuvant therapy for premenopausal women with early-stage, HR-positive breast cancer, Dr. Rugo proposed a new algorithm for therapeutic selection in this setting, based largely on data from the SOFT, TEXT, and ABCSG-12 trials.1-3
Low-risk disease: ≥5 years of tamoxifen
In the SOFT/TEXT analyses, 5-year breast cancer-free interval (BCFI) rates of approximately 97% were reported among women with low-risk clinicopathologic features (ie, smaller tumors, node-negative, grade 1, age ≥40 years) who did not receive chemotherapy.
Intermediate-risk disease: Chemotherapy, followed by ovarian function suppression (OFS) plus tamoxifen or exemestane, or OFS plus endocrine therapy.
There is some evidence suggesting that a subgroup of women with intermediate-risk disease (low-grade disease with larger tumor or low-grade, node-positive disease) benefit as much from OFS and exemestane or tamoxifen as they do from chemotherapy. More guidance on how to treat these patients will come from the TAILORx, RxPONDER (S1007), and MINDACT trials.4-6
High-risk disease: Chemotherapy should be given to women with high-risk disease (larger tumor, node-positive, grade 3, age <35 years), followed by OFS plus exemestane or tamoxifen.
Data from the SOFT/TEXT trials suggest that OFS plus tamoxifen or exemestane is superior to tamoxifen monotherapy (particularly in women age <35 years) for high-risk disease (absolute improvement in 5-year BFCI vs tamoxifen: OFS plus exemestane, 16%; OFS plus tamoxifen, 11%). Moreover, OFS plus exemestane is superior to OFS plus tamoxifen in terms of 5-year breast cancer-free interval (BCFI) and distant recurrence-free interval (DFCI).
Dr. Rugo noted that the follow-up for DFCI and overall survival from the SOFT and TEXT trials are relatively short at 5 years and with about 50% of clinical events reported. Clinical management will be aided by longer follow-up data. Additionally, accrual for these trials was conducted prior to the widespread clinical implementation of genomic testing.
Dr. Rugo emphasized the importance of individualizing treatment planning, with particular consideration and management of toxicity during decision making. In the SOFT trial, 22% of patients discontinued OFS therapy by 3 years; however, she noted, these patients still derived benefit. Depression and menopausal symptoms are the most marked symptoms of OFS therapy. Younger women are most likely to experience toxicity from endocrine therapy. Offering young women endocrine therapy immediately after chemotherapy, before ovarian function is restored, is generally more tolerable than initiating OFS after ovarian function has resumed post-chemotherapy.
- Pagani O et al; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer [published online June 1, 2014]. N Engl J Med. 2014;371:107-118.
- Francis PA, Regan MM, Fleming G, et al; for the SOFT Investigators and the International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372:436-446.
- Gnant M, Mlineritsch B, Stoeger H, et al; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015;36:313-320.
- ClinialTrials.gov website. Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer. ClinicalTrials.gov Identifier: NCT01272037.
- ClinialTrials.gov website. Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial). ClinicalTrials.gov Identifier: NCT00310180.
ClinialTrials.gov website. Genetic Testing or Clinical Assessment in Determining the Need for Chemotherapy in Women With Breast Cancer That Involves No More Than 3 Lymph Nodes. ClinicalTrials.gov Identifier: NCT00433589.
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PER Pulse™ Recap
32nd Annual Miami Breast Cancer Conference®
Sequencing of Adjuvant Therapies for Advanced HER2-Positive Breast Cancer
The multidisciplinary Miami Breast Cancer Conference® has been bringing together surgical, medical, and radiation oncologists for 32 years, with the aim of fostering awareness of the state-of-the-art treatments in each therapeutic area and encouraging cross-team cooperation in the clinic. This third of 3 PER Pulse™ Recaps that is focused on the 32nd Annual Miami Breast Cancer Conference® examines sequencing of adjuvant therapies for advanced HER2-positive breast cancer, as discussed by Dr. Mark Pegram.
Dr. Mark Pegram summarized regimens currently preferred for HER2-positive metastatic breast cancer (MBC):
- First-line: Pertuzumab plus trastuzumab plus docetaxel [evidence-based]1,2
- Second-line: T-DM1 (for trastuzumab-exposed patients) [evidence-based]1,2
- Third-line: Lapatinib plus capecitabine (presuming patient already received T-DM1) or other combination of chemotherapy, and trastuzumab, lapatinib and trastuzumab, or hormonal therapy (in patients with hormone receptor [HR]-positive disease) [consensus-based]2
- Beyond: Clinical trial; chemotherapy plus trastuzumab
These recommendations are based primarily on results from the phase III CLEOPATRA,3 EMILIA,4 and MARIANNE trials.5 Dr. Pegram noted that, as always, therapeutic selection and management must be individualized. Other regimens should be considered and discussed as needed.
The benefits of dual anti-HER2 blockade with trastuzumab and pertuzumab were demonstrated in the phase III CLEOPATRA trial of trastuzumab/placebo/docetaxel or trastuzumab/pertuzumab/docetaxel for HER2-positive MBC, and established pertuzumab-based regimens as the leading choice for MBC in the front line.1,2
The pivotal EMILIA trial randomized patients with locally advanced breast cancer (LABC) or MBC to salvage therapy with T-DM1 or capecitabine plus lapatinib.4 The co-primary endpoints of progression-free survival (PFS) and overall survival were both met, and T-DM1 was clearly less toxic than capecitabine plus lapatinib. These results led to FDA approval of this regimen for patients with advanced breast cancer who had received trastuzumab and taxane therapy.6
The phase III MARIANNE trial was initiated to build on results from a phase II randomized trial, which favored T-DM1 over trastuzumab plus docetaxel (PFS: 14.2 mo vs 9.2 mo; HR = 0.59; 95% CI, 0.36-0.97; P <.035), and evaluate efficacy of first-line T-DM1 for advanced HER2-positive breast cancer.7,8 MARIANNE randomized 1095 patients to trastuzumab plus taxane, T-DM1 plus pertuzumab, or T-DM1 plus placebo. Top-line data indicate that the trial met its noninferiority endpoint, with similar PFS across the 3 trial arms. Adverse events (AEs) observed in the 2 experimental arms were consistent with previous studies of T-DM1 and/or pertuzumab.5,9
Although T-DM1 is less toxic than cytotoxic-chemotherapy–based regimens, it is associated with thrombocytopenia, minor bleeding, and transaminase elevation. Patients should be monitored for these AEs, which can be mitigated with standardized dose modifications. Nodular regenerative hyperplasia is a very rare AE that is associated with portal hypertension, and requires discontinuation of T-DM1.10
Finally, Dr. Pegram reviewed potential regimens for use beyond a CLEOPATRA-like regimen and/or T-DM1 as first- and second-line treatments. Namely, he mentioned lapatinib-based regimens, endocrine therapy (for the nearly 50% of patients with HR–positive, HER2-positive disease), or enrollment in a clinical trial.1,2
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2015. March 11, 2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 21, 2015.
- Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guidelines [published online May 5, 2014]. J Clin Oncol. 2014;32:2078-2099. doi: 10.1200/JCO.2013.54.0948.
- Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-734.
- Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791.
- Ellis PA, Barrios CH, Eiermann W, et al. Phase III, randomized study of trastuzumab emtansine (T-DM1) ± pertuzumab vs trastuzumab + taxane for first-line treatment of HER2-positive MBC: primary results from the MARIANNE study. J Clin Oncol. 2015;33:(suppl; abstr 507).
- US Food and Drug Administration website. FDA approves new treatment for late-stage breast cancer. Press Release. February 22, 2013. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm340704.htm. Accessed May 20, 2015.
- Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer [published online February 4, 2013]. J Clin Oncol. 2013;31:1157-1163.
- ClinicalTrials.gov website. A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE). ClinicalTrials.gov Identifier: NCT01120184. https://clinicaltrials.gov/ct2/show/NCT01120184?term=NCT01120184&rank=1. Accessed May 20, 2015.
- Roche website. Roche provides update on phase III MARIANNE study in people with previously untreated advanced HER2-positive breast cancer. Press Release. December 19, 2014. http://www.roche.com/media/store/releases/med-cor-2014-12-19.htm. Accessed May 20, 2015.
Miles D, Wildiers H, Harbeck N, et al. Retrospective analysis of toxicity in patients (pts) with liver metastases (mets) from phase 3 studies of trastuzumab emtansine (T-DM1) in pts with metastatic breast cancer (MBC). J Clin Oncol. 2014;32(suppl 5s; abstr 609).
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