New Breast Cancer Treatment Strategies Highlighted at SABCS 2017
In This Article
- Ribociclib Added to First-Line Therapy Improves Outcomes in HR-Positive Advanced Breast Cancer
- Extending Aromatase Inhibitor Therapy by 2 Years Better Than 5 After Endocrine Therapy
- Nab-Paclitaxel Improves Disease-Free Survival in Early Breast Cancer
- Combining Pembrolizumab and Trastuzumab in Trastuzumab-Resistant HER2-Positive Breast Cancer Shows Promise
- Dose-Dense Chemotherapy Should Be a New Standard in Early Breast Cancer
- Adjuvant Trastuzumab Can Be Skipped in HER2-Low, High-Risk Breast Cancer
Key presentations featured during press conferences at the 2017 San Antonio Breast Cancer Symposium have important practical implications for oncologists and other providers who manage patients with breast cancer.
Ribociclib Added to First-Line Therapy Improves Outcomes in HR-Positive Advanced Breast Cancer
The addition of the cyclin-dependent kinase (CDK)4/CDK6 inhibitor ribociclib (Rubraca) to standard first-line endocrine therapy, with temporary ovarian suppression, significantly improved progression-free survival (PFS) for pre- and perimenopausal women with advanced hormone receptor (HR)-positive, HER2-negative breast cancer in the phase 3 MONALEESA-7 trial.
Although CDK4/CDK6 inhibitors are FDA approved for use in combination with hormonal therapy, such as aromatase inhibitor (AI) or fulvestrant, for postmenopausal women with advanced HR-positive, HER2-negative disease, this is the first randomized trial to show that this combination is also a good treatment option for younger pre- or perimenopausal women (approximately 40% of all HR-positive, HER2-negative advanced breast cancer).
“It is also the first trial to show that ribociclib can be safely and effectively combined with either tamoxifen or a nonsteroidal AI, together with ovarian suppression using goserelin,” said lead investigator Debasish Tripathy, MD, Department of Breast Medical Oncology, M.D. Anderson Cancer Center, Houston.
“This is a potential new treatment for premenopausal women with HR-positive, HER2-negative advanced breast cancer, regardless of disease-free interval or endocrine partner,” Dr Tripathy said.
Of the 672 patients enrolled in the study, 335 were randomized to ribociclib plus either tamoxifen or AI and goserelin, and 337 were randomized to the same hormonal therapy plus goserelin and placebo. The study met its primary end point: the median PFS was significantly better in the ribociclib arm at 23.8 months compared with 13 months in the placebo arm, representing a 45% improvement favoring ribociclib (P = 9.83 × 10–8).
The benefit of adding ribociclib to hormonal therapy was consistent across all patient subgroups, regardless of the endocrine therapy used. Safety was manageable and predictable. Patients who received ribociclib had a clinically meaningful improvement in the time to deterioration of quality of life and to improvement in pain score compared with the placebo arm.
Extending Aromatase Inhibitor Therapy by 2 Years Better Than 5 After Endocrine Therapy
Two years of additional AI therapy after 5 years of endocrine therapy were equally as effective as 5 additional years in the treatment of postmenopausal women with hormone receptor (HR)-positive breast cancer, according to the results of the large ABCSG-16 trial.
Extending AI therapy for 2 years or for 5 years achieved similar rates of disease-free survival (DFS), overall survival, time to contralateral breast cancer, and time to second primary cancer. The rate of clinical fracture was slightly higher in the 5-year arm, at 6%, versus 4.7% in the 2-year arm.
“We can now conclude that after 5 years of adjuvant endocrine therapy, 2 more years of AI are sufficient. There is no benefit from 5 additional years of AI, and 5 more years lead to more clinical fractures and should be avoided,” said lead investigator Michael Gnant, MD, Medical University of Vienna, Austria. “The take-home message is that we can avoid unnecessary treatment and side effects by giving only 2 years of additional AI instead of 5 years,” he said.
“There was no benefit in the highest-risk subgroups or for those who were adherent. For the vast majority of patients with luminal breast cancer, the most common type of breast cancer, a total of 7 years of additional AI is sufficient,” Dr Gnant said.
The study included 3484 women with HR-positive breast cancer who received 5 years of endocrine therapy (tamoxifen, AI, or tamoxifen followed by an AI) and were then randomized to 2 more years of anastrozole or to 5 more years of anastrozole. The median follow-up was 106.2 months.
“For many years, we have treated too many people for too long. De-escalation of therapy is a trend for HER2-positive and estrogen receptor–positive breast cancer. This is all good news. We don’t need another randomized trial to prove we are not depriving patients with only 7 years of adjuvant endocrine therapy,” said Carlos L. Arteaga, MD, Director, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, who moderated the press conference.
Nab-Paclitaxel Improves Disease-Free Survival in Early Breast Cancer
Substituting nab-paclitaxel (Abraxane) for paclitaxel (Taxol) as part of neoadjuvant chemotherapy improved DFS in patients with high-risk early breast cancer over the long-term, in the phase 3 clinical trial GeparSepto.
This large study, conducted at 69 centers, randomized 1200 patients with nonmetastatic early breast cancer to 12 weekly cycles of paclitaxel or of nab-paclitaxel, each followed by 4 cycles of epirubicin plus cyclophosphamide. All patients with HER2-positive disease also received trastuzumab and pertuzumab therapy.
The patient and tumor characteristics were well-balanced between the 2 treatment arms.
The 3-year DFS rate was 87.1% with nab-paclitaxel versus 80.7% with standard paclitaxel (hazard ratio, 0.69; 95% confidence interval, 0.54-0.89; P = .0044). The absolute difference between the treatment groups was 6.4%. At 4 years, the DFS rates were 83.5% with nab-paclitaxel and 76.2% with paclitaxel, respectively, for an absolute improvement of 7.3%.
A subgroup analysis showed that nab-paclitaxel improved DFS in all subgroups, including biologic subtype, HER2 status, estrogen receptor/progesterone receptor status, and low versus high Ki67.
The overall survival data are not yet mature.
“These long-term data are important, because so far 61% of the DFS events that have occurred in GeparSepto are distant relapses,” said Andreas Schneeweiss, MD, Head, Division of Gynecological Oncology, University Hospital, Heidelberg, Germany, who presented the data.
At another session, Eric P. Winer, MD, Director, Breast Oncology Center, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, said that he needs more data before substituting nab-paclitaxel for paclitaxel as part of adjuvant or neoadjuvant therapy in routine clinical practice.
“I would not use this outside of a clinical trial,” Dr Winer said. He noted that the approved dose is too high, and that lower doses can reduce toxicity.
Combining Pembrolizumab and Trastuzumab in Trastuzumab-Resistant HER2-Positive Breast Cancer Shows Promise
The combination of pembrolizumab (Keytruda) plus trastuzumab (Herceptin) was well-tolerated and provided clinical benefit in patients with trastuzumab-resistant, HER2-positive advanced breast cancer in the phase 1b/2 PANACEA trial.
The combination of pembrolizumab and trastuzumab met its primary end point, with an objective response rate (ORR) of 15% and a disease control rate of 25% at ≥6 months among 58 patients with HER2-positive, advanced breast cancer that had become resistant to trastuzumab. The median follow-up was 13.6 months.
Patients with PD-L1–positive disease who have ≥5% circulating tumor-infiltrating lymphocytes have the best response to the immunotherapy combination. In a subgroup of 40 patients with PD-L1–positive disease and ≥5% tumor-infiltrating lymphocytes in the metastatic lesion, the ORR was 39%, and the disease control rate was 47%.
This suggests that quantifying tumor-infiltrating lymphocytes can select patients who will derive the most benefit from this combination. No responses were observed in the 18 patients with PD-L1–negative disease.
“This proof-of-principle study suggests that immune evasion is a mechanism of resistance to trastuzumab and contributes to disease progression in advanced HER2-positive breast cancer,” said lead investigator Sherene Loi, MBBS (Hons), PhD, FRACP, Head, Translational Breast Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.
“These are the best data we have on immunotherapy in HER2-positive breast cancer. If future studies pan out, we will have more options to treat this disease. This study gives us a good signal to continue to study immunotherapy in HER2-positive disease in combination with anti-HER2 therapy,” commented Virginia G. Kaklamani, MD, Leader, Breast Cancer Program, University of Texas Health Cancer Center, San Antonio.
Dose-Dense Chemotherapy Should Be a New Standard in Early Breast Cancer
Increasing the dose density of chemotherapy should become a new standard for the treatment of early breast cancer, according to a large meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group. This meta-analysis included individual patient data from 25 clinical trials, with a total of 34,122 women.
The analysis showed that approaches to dose intensification (ie, shortening the intervals between chemotherapy cycles or giving chemotherapy sequentially) significantly reduced the rate of recurrence and breast cancer mortality compared with standard chemotherapy.
A pooled analysis of all 25 dose-intensification trials showed 10-year recurrence rates of 32% with standard chemotherapy versus 28.4% with dose-dense chemotherapy (P <.0001). The 10-year rate of breast cancer mortality was 22.2% with standard chemotherapy versus 19.5% with dose-dense chemotherapy (P <.0001).
Although these improvements seem modest overall, lead investigator Richard Gray, MSc, Programme Leader, Medical Research Council Population Health Research Unit, University of Oxford, England, said, “Chemotherapy reduces mortality by one-third, and dose-dense chemotherapy reduces it by a further 13%, amounting to incremental reductions that nearly cut in half the number of breast cancer deaths.”
Adjuvant Trastuzumab Can Be Skipped in HER2-Low, High-Risk Breast Cancer
The addition of trastuzumab (Herceptin) to standard adjuvant chemotherapy did not improve DFS in women with early-stage, high-risk invasive breast cancer and low levels of HER2 expression on immunohistochemistry or in situ hybridization, according to the results of the NSABP-B-47 trial. Patients with “low HER2” levels represent approximately 45% of patients with early breast cancer and are currently not receiving trastuzumab. Although some studies suggest such patients may benefit from anti–HER2-targeted therapy, this large study failed to show any benefit.
“It is important to know that current guidelines defining HER2-positive status are valid and ensure that no patients are over- or undertreated. Trastuzumab has serious adverse events, and this study can spare patients from these effects,” said lead investigator Louis Fehrenbacher, MD, an oncologist at Vallejo Medical Center, Kaiser Permanente, California.
The study enrolled 3270 patients with early breast cancer and low HER2 (IHC1+, IHC2+, and/or ISH-negative). Patients were randomized in a 1:1 ratio to standard adjuvant chemotherapy with or without trastuzumab. The 5-year invasive DFS rate was 89.6% in patients treated with trastuzumab versus 89.2% among those who did not receive trastuzumab.