The availability of scalp-cooling devices will offer a new option, backed by evidence, for our patients who are concerned about hair loss during adjuvant therapy for early-stage breast cancer. Each oncology practice and cancer center will have to determine how this system will fit into its workflow.— Jame Abraham, MD
Each year, The ASCO Post asks Jame Abraham, MD, Director of the Breast Oncology Program at Taussig Cancer Institute and Co-Director of the Cleveland Clinic Comprehensive Breast Cancer Program, to give his picks for the most important research presented at the San Antonio Breast Cancer Symposium. The following are his choices in five key areas—adjuvant, metastatic, and neoadjuvant settings; radiation oncology; and supportive care—along with reflections on a memorable lecture from the 2016 meeting. Dr. Abraham’s comments on these presentations appear in italics.
Benefit of Extended Adjuvant Endocrine Therapy Questioned
Extended endocrine therapy with an aromatase inhibitor did not improve disease-free survival in patients with hormone receptor–positive breast cancer enrolled in three studies. The results stand in contrast to the phase III National Cancer Institute of Canada (NCIC) MA.17R study showing benefit for the extended use of adjuvant letrozole beyond 5 years.1
NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP) B-42 evaluated 5 years of letrozole vs placebo in 3,966 patients.2 Although the study showed a 15% reduction in the risk of progression, the difference was not statistically significant. Disease-free survival at 7 years was 84.7% with extended letrozole vs 81.3% with placebo (hazard ratio [HR] = 0.85, P = .048 [not significant]). There were, however, significant improvements in the rates of distant metastasis, contralateral breast cancer, and breast cancer–free interval events in B-42.
The phase III European IDEAL and DATA trials also failed to show benefits for extended adjuvant hormonal treatment. IDEAL compared a total of 7.5 vs 10 years of aromatase inhibitor therapy.3 Disease-free survival rates were 88.4% vs 87.9%, respectively (HR = 0.06, P = .70), and the overall survival rate was approximately 93% in each arm. DATA evaluated extended anastrozole therapy in women who had received 2 to 3 years of adjuvant tamoxifen.4 Five-year disease-free survival was 83.1% for patients receiving 6 additional years and 79.4% after 3 additional years of anastrozole. The total of 8 years of endocrine therapy reduced the risk by 21%, which was not statistically significant (P = .07).
Based on these findings, clinicians might consider carefully assessing the potential risks and benefits before recommending extended endocrine therapy. The data from these studies suggest we should individualize treatment.
In high-risk patients (based on clinical features or genomic testing such as the Breast Cancer Index), we should discuss the pros and cons of continuing beyond 5 years with aromatase inhibitors. In patients who have significant side effects, such as joint pain, osteopenia, and those who are at low risk, it is reasonable to stop treating with aromatase inhibitors after 5 years, based on the available data.
Everolimus Plus Fulvestrant: A New Option
The phase II PrECOG 0102 trial evaluated the estrogen receptor downregulator fulvestrant (Faslodex) plus the mTOR inhibitor everolimus (Afinitor) in postmenopausal women with hormone receptor–positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitors.5 The study documented a doubling in median progression-free survival, from 5.1 months with fulvestrant alone to 10.4 months with the combination. This represents a 40% improvement, which was statistically significant (P = .02). The combination did lead to more toxicity, but it can be considered a new option for second-line therapy after endocrine resistance develops.
With fulvestrant plus everolimus, grade 3 adverse events were more frequent (48% vs 14%), the most common being stomatitis (9%), pneumonitis (6%), fatigue (5%), and hyperglycemia (6%). Prophylactic corticosteroid mouthwash has since been shown to reduce the risk of stomatitis.
Fulvestrant plus everolimus represents a potentially new option for postmenopausal hormone receptor–positive breast cancer that becomes resistant to endocrine therapy. The combination significantly reduced the risk of progression but did increase side effects, which could still be a major problem for a significant number of patients.
This trial gives us data for combining fulvestrant with everolimus in the second-line setting. But with the availability of cyclin-dependent kinase (CDK) 4/6 inhibitors such as palbociclib (Ibrance) in the first-line and second-line settings, I am not sure how this combination will fit into the management of metastatic estrogen receptor–positive breast cancer.
Abemaciclib Plus Fulvestrant Reduces Ki67 Expression
In a phase II trial, neoadjuvant treatment with the investigational CDK4/6 inhibitor abemaciclib, either alone or in combination with anastrozole, reduced the levels of Ki67, a marker of cell proliferation, in hormone receptor–positive, HER2-negative breast cancer cells, compared with anastrozole alone.6 Patients received neoadjuvant therapy with anastrozole, abemaciclib, or anastrozole plus abemaciclib for 2 weeks. All patients then received anastrozole plus abemaciclib for 14 weeks, followed by surgery.
After the first 2 weeks of neoadjuvant therapy, the mean change in Ki67 expression was significantly greater for both arms containing abemaciclib: –92.6% for abemaciclib/anastrozole, –90.6% for abemaciclib alone, and –63.2% for anastrozole alone (P < .001 for abemaciclib arms vs anastrozole).
The measurable biologic effect of this CDK4/6 inhibitor may be important. Reduced Ki67 levels have been shown in other studies to correlate with improved outcomes. The data therefore suggest that CDK4/6 inhibitors may benefit patients with early-stage disease, though this is still only a proof-of-concept study. Clinical outcomes, including pathologic complete response, have not been assessed, and the immediate clinical application of these data is limited.
The study confirms, however, that CDK4/6 inhibitors will continue to change the landscape of estrogen receptor–positive breast cancer from the metastatic to the neoadjuvant setting. This is very good news for our patients. I am sure that in the next 3 to 5 years, these agents will emerge as the drug of choice in patients with estrogen receptor–positive disease, and we will be using less and less chemotherapy.
Radiotherapy May Increase Complications After Implant Reconstruction
Postmastectomy radiation therapy increased the risk for complications in patients who received implant-based breast reconstruction, in a large prospective study.7 It also impaired patient-reported satisfaction with reconstructed breasts with implants. Radiotherapy did not, however, cause problems (such as hematoma and wound infection) in patients who underwent autologous reconstruction.
The Mastectomy Reconstruction Outcomes Consortium collected data from more than 2,000 women who did or did not receive radiotherapy after mastectomy and underwent either implant or autologous reconstruction. After 2 years of follow-up, 34% of patients who received radiotherapy and 22% of patients who did not receive radiotherapy experienced reconstruction-related complications.
In a multivariable analysis, the impact of radiotherapy differed by type of reconstruction. Radiotherapy more than doubled the odds of developing complications in patients who received implants but was not associated with complications after autologous reconstruction. Patient-reported satisfaction was also significantly lower in patients with implants who received radiation.
Radiotherapy provides benefits postmastectomy in many, if not most, cases of early breast cancer, but it may affect the options and outcomes for breast reconstruction. Since many such patients become long-term survivors, breast reconstruction can have a lasting impact on quality of life. We have not yet established the optimal approach for integrating postmastectomy radiotherapy and breast reconstruction.
While this study is observational and does not prove cause-and-effect, the data could help physicians and patients make treatment-related decisions. Up to now, we had only very limited data about complications from radiation therapy after reconstruction. Now we can discuss risks and benefits with our patients, with the support of data.
When selecting the type of reconstruction, women who will receive postmastectomy radiation therapy should be informed of the risks suggested by this study for implant reconstruction. Those who pursue autologous reconstruction and are debating whether to have radiotherapy can derive some reassurance from the findings.
Scalp Cooling Prevents Alopecia
A system designed to prevent alopecia in chemotherapy patients by cooling the scalp via a fitted “cold cap” was able to reduce hair loss in more than half the breast cancer patients tested in a prospective multicenter randomized trial.8 Researchers evaluated the Orbis Paxman Hair Loss Prevention System in 232 women with early breast cancer who were planning to undergo anthracycline- or taxane-based chemotherapy. Patients randomized to scalp cooling used the system before, during, and after chemotherapy sessions.
Hair loss, as assessed by independent evaluators based on published criteria, was reduced by 50.5% in the scalp-cooling group, compared to 0% in the control arm. Side effects were mild and included discomfort and headache. The results surpassed the superiority boundary and prompted the researchers to stop the study early.
In Europe, scalp-cooling technology has helped many patients keep their hair during chemotherapy. There has been a lot of interest in scalp cooling in the United States, but the technology has been slow to catch on. This is partially due to concerns over cost and the possible potentiation of metastasis to the scalp.
In December 2015, the U.S. Food and Drug Administration (FDA) approved the DigniCap, and now the manufacturer of the Orbis Paxman Hair Loss Prevention System —evaluated in this study—is also seeking FDA approval. The researchers maintained that this system keeps a more constant temperature, requires only one cap rather than several during a session, and allows for freedom of movement. Women in the study will continue to be monitored for cancer recurrence and metastasis to the scalp.
This is the first prospective randomized trial supporting hair preservation in early-stage breast cancer. Data will be submitted to the FDA, and after the approval process, the manufacturer will need to figure out a reimbursement model in the United States. The availability of scalp-cooling devices such as the Orbix Paxman will offer a new option, backed by evidence, for our patients who are concerned about hair loss during adjuvant therapy for early-stage breast cancer. Each oncology practice and cancer center will have to determine how this system will fit into its workflow.
William L. McGuire Memorial Lecture
The annual William L. McGuire Memorial Lecture was delivered this year by Dr. Eric P. Winer, of Dana-Farber Cancer Institute, Boston. He titled his talk, “The Long and Winding Road: Glancing Back, but Moving Forward.”
In addition to the usual type of content for named lectures—discussion of how far the field has come and where the field is going—Dr. Winer eloquently shared some very personal revelations. The road has truly been “winding” for him, as he very candidly revealed in describing his battle with his own health issues. All who were fortunate enough to attend his presentation left very inspired by his message—the importance of coping well, the burden of stigma, the need for hope, and belief in science.
I routinely listen to fascinating TED talks. But I found that Dr. Winer, who is one of the most respected breast cancer researchers, shared a life story that was truly amazing and inspiring on a different level. He is one of us. I really admire his courage to discuss his personal struggles in public. His life is a testament to his belief in science, humanity, and optimism.
The ASCO Post will follow-up with an interview of Dr. Winer in a future issue. ■
Disclosure: Dr. Abraham has been a speaker for Pfizer and Genentech.
1. Goss PE, Ingle JN, Pritchard KI, et al: A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. 2016 ASCO Annual Meeting. Abstract LBA1. Presented June 5, 2016.
2. Mamounas EP, Bandos H, Lembersky BC, et al: A randomized, double-blinded, placebo-controlled clinical trial of extended adjuvant endocrine therapy with letrozole in postmenopausal women with hormone-receptor-positive breast cancer who have completed previous adjuvant treatment with an aromatase inhibitor. 2016 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 7, 2016.
3. Block EJ, Van de Velde CJH, Meershoek-Klein Kranenbarg EM, et al: Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy. 2016 San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 7, 2016.
4. Tjan-Heijnen VC, Van Hellemond IE, Peer PG, et al: First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer. 2016 San Antonio Breast Cancer Symposium. Abstract S1-03. Presented December 7, 2016.
5. Kornblum N, Manola J, Klein P, et al: PrECOG 0102: A randomized, double-blind, phase II trial of fulvestrant plus everolimus or placebo in post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitor therapy. 2016 San Antonio Breast Cancer Symposium. Abstract S1-02. Presented December 7, 2016.
6. Hurvitz S, Martin M, Fernandez Abad M, et al: Biological effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with hormone receptor-positive, HER2-negative breast cancer. 2016 San Antonio Breast Cancer Symposium. Abstract S4-06. Presented December 8, 2016.
7. Jagsi R, Momoh AO, Qi J, et al: Impact of radiotherapy on complications and patient-reported satisfaction with breast reconstruction. 2016 San Antonio Breast Cancer Symposium. Abstract S3-07. Presented December 8, 2016.
8. Nangia JR, Wang T, Niravath PA, et al: Scalp Cooling Alopecia Prevention trial (SCALP) for patients with early stage breast cancer. 2016 San Antonio Breast Cancer Symposium. Abstract S5-02. Presented December 9, 2016.