Jame Abraham, MD, FACP
Each year, The ASCO Post asks Jame Abraham, MD, FACP, Director of the Breast Oncology Program at Taussig Cancer Institute and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine, to offer his picks for the most important research presented at the 2018 San Antonio Breast Cancer Symposium. The following are his choices for and comments about studies that may be practice-changing. Dr. Abraham’s comments on these presentations appear in italics.
T-DM1 vs Trastuzumab in KATHERINE Trial
The phase III KATHERINE trial randomly assigned 1,486 patients with residual HER2-positive breast cancer after neoadjuvant therapy to continue trastuzumab or be switched to trastuzumab emtansine (T-DM1).1 T-DM1 reduced the risk of an invasive disease–free survival event at 3 years by 50%. At 3 years, invasive disease–free survival was 77.0% with trastuzumab vs 88.3% with T-DM1 (hazard ratio [HR] = 0.50; P < .0001). The 11% absolute increase in invasive disease–free survival was actually better than the investigators had predicted, and the Kaplan-Meier curves separated early and tended to widen with follow-up.
Clinicians should remember that although T-DM1 is generally well tolerated, some patients have side effects.— Jame Abraham, MD, FACP
Tweet this quote
All prespecified subgroups benefited from T-DM1, including patients with both operable (HR = 0.47) and inoperable cancer (HR = 0.54), hormone receptor–negative (HR = 0.50) and hormone receptor–positive (HR = 0.48) cancer, node-positive (HR = 0.52) and node-negative (HR = 0.44) disease, and very small residual disease with negative nodes (HR = 0.60). The striking homogeneity of benefit across all the major subgroups was considered one of the remarkable findings of the study. The secondary endpoints of disease-free survival and distant recurrence–free interval also showed meaningful reductions in first events with T-DM1. Breast cancer experts agreed that these findings change the standard of care in this patient population, and there will be less tendency to use pertuzumab plus trastuzumab.
Dr. Abraham: The results of KATHERINE build upon earlier findings for T-DM1. In the EMILIA trial,2 T-DM1 improved progression-free survival and overall survival vs lapatinib/capecitabine, and in TH3RESA, these outcomes were improved as compared to trastuzumab plus physician’s choice of chemotherapy.3 The results were more modest in the MARIANNE trial,4 where T-DM1 did not outperform taxane/trastuzumab combinations, and surprisingly, the addition of pertuzumab to T-DM1 did not increase benefit over T-DM1 alone.
Although MARIANNE tempered the enthusiasm about T-DM1, the KATHERINE trial has brought renewed attention to this drug. Moreover, it has propelled T-DM1 to the front of the line for patients with HER2-positive residual disease after neoadjuvant therapy. All subsets benefited, including patients with any degree of residual disease. In my view, KATHERINE will change practice overnight (pending U.S. Food and Drug Administration [FDA] approval), much as adjuvant trastuzumab did after we heard results of the NSABP B-31 and NCCTG 9831 trials.5 T-DM1 will now be further explored for other patients with early-stage breast cancer.
Clinicians should remember that although T-DM1 is generally well tolerated, some patients have side effects. We must be careful not to ignore the potential for neuropathy, fatigue, and hepatic toxicity, especially over the long term. Considering the magnitude of the benefit with this drug, I believe many patients will be willing to pay the price.
Low-Dose Tamoxifen for Intraepithelial Neoplasia
A verylow dose of tamoxifen—5 mg/d, given for 3 years rather than 5 years—halved the risk of breast cancer recurrence or new lesions over placebo in women with breast intraepithelial neoplasia (ductal carcinoma in situ [DCIS], atypical ductal hyperplasia, lobular carcinoma in situ [LCIS]), without producing the usual toxicities seen with the standard dose, investigators from the phase III Italian TAM01 trial reported.6 After a median follow-up of 5.1 years, 5.5% of patients in the low-dose tamoxifen arm and 11.3% in the placebo arm had disease recurrence or new disease in the breast (HR = 0.48; P = .024). Contralateral breast cancer developed in 12 (4.8%) and 3 (1.2%) patients, respectively (HR = 0.24; P = .018).
For more on the studies presented at the San Antonio Breast Cancer Symposium, look for these and other interviews on The ASCO Post Newsreels at www.ascopost.com:
The use of low-dose tamoxifen was associated with an average of only one additional hot flash per day and no increase in the daily hot flash score. Reports of vaginal dryness, pain on intercourse, and musculoskeletal pain or arthralgia were not significantly different, and treatment adherence was similar to that seen in placebo recipients. Low-dose tamoxifen can be taken as 5 mg/d (splitting a 10-mg tablet) or 10 mg every other day.
Dr. Abraham: Although tamoxifen is effective in preventing breast cancer recurrence, its side effects—menopausal symptoms, endometrial cancer, deep-vein thrombosis, and pulmonary embolism—are barriers to its use as a preventive measure. The aim of this noninferiority study was to determine whether a lower dose and shorter duration of tamoxifen would be as efficacious as and better tolerated than the standard dose. It was a reasonable trial to conduct, considering that the recommended dose of tamoxifen was arbitrarily set, and the optimal dose is actually unknown.
The cumulative incidence of breast events at 5 years was 6.4% with low-dose tamoxifen and 11.0% with placebo, and the incidence of serious adverse events was 0.87% and 0.41%, respectively. The benefit found in this study translates into a number needed to treat of 22 and a number needed to harm of 218, which is very favorable.
These findings tell me that I may be able to safely reduce the dose for patients who do not tolerate tamoxifen, which could help me keep patients on treatment. Clearly, the side-effect profile of tamoxifen and aromatase inhibitors has given the antiestrogens something of a bad reputation, especially for chemoprevention. It’s unclear whether the use of lower doses of tamoxifen can change that, but if we can find ways to enhance tolerability so that patients will accept tamoxifen therapy, that will be a very positive development.
Small Differences in Recurrence With Partial-Breast vs Whole-Breast Irradiation
Partial-breast irradiation delivered over 5 to 10 days did not meet noninferiority criteria compared with whole-breast irradiation given over 5 to 7 weeks, according to the 10-year results of the large NRG (NSABP B-39/RTOG 0413) trial.7 However, the absolute 10-year cumulative difference in invasive breast tumor recurrence between the two treated groups was less than 1%, and the absolute cumulative difference in relapse-free interval was 1.6%.
The NRG study enrolled 4,216 patients with DCIS or stage I or II invasive breast cancer with 0 to 3 positive lymph nodes who, after lumpectomy, were randomly assigned to partial-breast irradiation prior to adjuvant chemotherapy (twice daily treatment with 3.4–3.85 Gy, totaling 10 treatments delivered over 5–10 days using 3-dimensional [3D] conformal external-beam radiotherapy or brachytherapy) or whole-breast irradiation after adjuvant chemotherapy (twice daily treatment with 2 Gy of radiation, to a total of 50 Gy with a sequential boost to the surgical site given over 5–7 weeks). Invasive recurrences were observed in 4.6% of the partial-breast irradiation group and 3.9% of the whole-breast irradiation group, for a 0.7% absolute difference that did not meet the hazard ratio for noninferiority. As expected, recurrences outside of the primary but still within the breast were more common with partial-breast irradiation.
There may be a misconception, among both physicians and patients, that with cancer treatment, ‘more is better,’ and partial-breast irradiation is therefore underutilized.— Jame Abraham, MD, FACP
Tweet this quote
The 10-year cumulative rate of relapse-free interval was 91.4% with partial-breast irradiation and 93.4% with whole-breast irradiation, an absolute difference of 1.6% that significantly favored whole-breast irradiation (P = .02). The difference in the 10-year rate of distant disease–free survival, 96.7% vs 97.1%, respectively, was not statistically significant, nor was the difference in the 10-year overall survival, which was 90.6% and 91.3%, respectively. Grade ≥ 3 toxicities were more common with partial-breast irradiation (though not significantly different), as were radiation-induced second cancers. Data on quality of life and cosmesis were not yet available.
Dr. Abraham: This is the largest trial to compare these radiotherapy techniques, and the differences in recurrence-free interval between the two arms, although statistically different, is small, and survival is the same. The authors said that the differences were even smaller in patients receiving partial-breast irradiation via the 3D technique (the more contemporary approach), though the study did not compare three methods. I think the findings, therefore, support the option of partial-breast irradiation for patients with early-stage breast cancer who want to undergo breast-conserving surgery, as per the 2016 American Society for Radiation Oncology (ASTRO) Guidelines.8
There may be a misconception, among both physicians and patients, that with cancer treatment, “more is better,” and partial-breast irradiation is therefore underutilized. For patients, however, the two approaches vary considerably in convenience and quality of life, as there is a dramatic difference in treatment duration of 5 to 7 weeks vs 5 to 10 days. This study suggests partial-breast irradiation is safe and effective, and we should be offering it to our patients more often.
Axillary Radiotherapy Is Safe and Effective After Positive Sentinel Node Biopsy
Following identification of a positive sentinel lymph node, surgical axillary lymph node dissection (ALND) and axillary radiation therapy provide excellent and comparable locoregional control and survival, but axillary radiotherapy results in significantly less lymphedema, according to 10-year follow-up of the large AMAROS trial.9 In AMAROS, axillary radiotherapy and ALND provided excellent and comparable overall survival, distant metastasis–free survival, and locoregional control.
AMAROS enrolled 4,806 patients with invasive breast tumors measuring 0.5 to 5 mm that were clinically node-negative. All patients underwent breast-conserving surgery or mastectomy, followed by sentinel node biopsy. The 29.7% of patients with a positive sentinel node were further randomized to ALND (n = 744) or axillary radiation therapy (n = 681). The mean number of sentinel nodes removed in both arms was two.
Since some women need more treatment and some need less, oncologists and surgeons need to tailor therapy according to the individual….— Jame Abraham, MD, FACP
Tweet this quote
At 10 years, recurrence rates were low and similar between the arms: 0.93% after ALND vs 1.82% after axillary radiation therapy. The rate of second primary cancers was higher in the axillary radiation therapy arm (12.09% vs 8.33%; P =. 035). Side effects were significantly lower in the axillary radiation therapy arm; 5 years after sentinel node biopsy, lymphedema was present and/or treated in about 30% of the ALND arm and about 15% in the axillary radiation therapy arm.
Dr. Abraham: Five-year outcomes of the AMAROS study were reported in 2013, showing no differences in relapse between surgery and radiation therapy but less lymphedema with axillary radiation therapy. The study was criticized as being underpowered to show a difference, due to short follow-up and few events. Now we have the 10-year analysis confirming these findings. We also have several other large trials providing reassurance that we do not have to remove all the lymph nodes if the sentinel node is positive and the nodal metastasis is small (not bulky). ACOSOG Z-0011, for one, provided convincing evidence—comparable 10-year outcomes—for de-escalating surgery in patients with a positive sentinel lymph node biopsy and clinically negative nodes.10
We can now be sure that de-escalation of therapy reduces the risk of morbidity for our patients without compromising their outcomes. Since some women need more treatment and some need less, oncologists and surgeons need to tailor therapy according to the individual, but I hope surgeons will begin to pay more attention to studies such as AMAROS, so that our patients can come through treatment with a better quality of life.
Circulating Tumor Cell Counts Useful in Some Breast Cancer Scenarios
In Patients with estrogen receptor–positive, HER2-negative metastatic breast cancer in whom the benefit of chemotherapy is uncertain, the use of circulating tumor cell (CTC) counts may have some value, according to data from a large French randomized trial that evaluated whether CTC counts can help personalize the decision to treat with endocrine therapy or chemotherapy.11 The study concluded that in patients with ≥ 5 CTC/7.5 mL, chemotherapy is preferred over endocrine therapy, and that CTC count can be helpful when treatment decisions are discordant.
The 778 patients were randomly assigned to treatment based on a clinical decision vs treatment according to CTC values (< 5 CTC/7.5 mL for choice of hormone therapy and ≥ 5 CTC/7.5 mL for chemotherapy). Patients with low CTC values were viewed as having a good prognosis and were treated with hormone therapy only, whereas those with high values received chemotherapy. The study met its primary endpoint, showing that progression-free survival was not inferior in the CTC-driven arm, compared with the clinically driven arm.
In 303 patients, there was disagreement as to the best treatment, and in this discordant group the use of CTCs to guide therapy led to a trend for superior outcomes with front-line chemotherapy. Chemotherapy as the chosen treatment in this group reduced disease progression risk by 44% over hormone therapy (HR = 0.66; P = .001), based on a median progression-free survival of 10.5 months with hormone therapy and 15.6 months with chemotherapy. At 2 years, overall survival was also significantly improved (HR = 0.65; P = .04), from 74.4% to 82.9%. Conversely, when concordance was high between the two decision modes, the two types of treatment yielded similar progression-free survival and overall survival.
Dr. Abraham: This is the first contemporary study reporting a significant survival benefit by doing CTC testing and the first to show a reduction in the risk of death with front-line chemotherapy. The results suggest that where clinician’s choice and CTC-based recommendations are discordant, there is a slight advantage for chemotherapy. Especially in patients with unfavorable characteristics (such as high CTC count), front-line chemotherapy can be a suitable option.
One concern is that the study did not incorporate cyclin-dependent kinase 4/6 inhibitors; therefore, the patients were not treated with a contemporary approach. Also, in the metastatic setting, we are mostly trying to de-escalate therapy, so the idea of giving chemotherapy instead of endocrine therapy is contrary to that. But the study warrants further follow-up, and CTC testing deserves additional trials to determine how best to utilize this information.
Atezolizumab Combination in Metastatic Triple-Negative Disease
The phase III IMpassion130 trial, published in 2018 in TheNew England Journal of Medicine,12 found that in patients with metastatic triple-negative breast cancer the combination of front-line atezolizumab plus nab-paclitaxel significantly improved disease-free and overall survival. The results were most pronounced in programmed cell death ligand 1 (PD-L1)–positive (≥ 1% expression) disease, and an exploratory analysis reported in San Antonio confirmed there was no benefit from the immunotherapy combination (vs nab-paclitaxel alone) in patients who were PD-L1–negative.13
IMpassion130 is the first phase III study to demonstrate a survival benefit with immunotherapy in triple-negative breast cancer.— Jame Abraham, MD, FACP
Tweet this quote
In patients with PD-L1–negative disease, the median progression-free survival was identical with atezolizumab/nab-paclitaxel vs placebo/nab-paclitaxel: 5.6 months. By contrast, a 10-month improvement in disease-free survival was found in PD-L1–positive patients treated with the immunotherapy combination vs placebo plus nab-paclitaxel: 25.5 months vs 15.5 months. There was no significant effect of atezolizumab/nab-paclitaxel on overall survival in PD-L1–negative patients, whose median overall survival was 18.9 months for immunotherapy vs 18.4 months for chemotherapy. The results of the exploratory analysis of IMpassion130 support the use of atezolizumab plus nab-paclitaxel exclusively in PD-L1–positive triple-negative breast cancer.
Dr. Abraham: IMpassion130 is the first phase III study to demonstrate a survival benefit with immunotherapy in triple-negative breast cancer. The study showed a clinically meaningful progression-free survival and overall survival benefit in PD-L1–positive patients, with a nice separation of the survival curves, but not in PD-L1–negative patients. These results are somewhat surprising because studies in other types of cancer have shown a benefit for checkpoint inhibitor therapy in patients with very low levels of PD-L1 expression and PD-L1–negative disease.
This exploratory analysis of IMpassion130 demonstrated that PD-L1 expression in immune cells is a highly reliable predictor of response.— Jame Abraham, MD, FACP
Tweet this quote
This exploratory analysis of IMpassion130 demonstrated that PD-L1 expression in immune cells is a highly reliable predictor of response. They support routine testing for PD-L1–positive status in patients with newly diagnosed metastatic and unresectable locally advanced triple-negative disease, to determine whether they can benefit from atezolizumab plus nab-paclitaxel. Pending FDA approval, these findings will change the practice for triple-negative PD-L1 (immune cell)–positive patients. ■
DISCLOSURE: Dr. Abraham reported no conflicts of interest.
1. Geyer CE, Huang C-S, Mano MS, et al: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE (NSABP B-50-1, GBG 77, and Roche BO27938). 2018 San Antonio Breast Cancer Symposium. Abstract GS1-10. Presented December 5, 2018.
2. Verma S, Miles D, Gianni L, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783-1791, 2012.
3. Krop IE, Kim SB, Martin AG, et al: Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): Final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 18:743-754, 2017.
4. Perez EA, Barrios C, Eiermann W, et al: Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: Primary results from the phase III MARIANNE study. J Clin Oncol 35:141-148, 2017.
5. Perez EA, Romond EH, Suman VJ, et al: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patients with HER2-positive breast cancer. 2007 ASCO Annual Meeting. Abstract 512.
6. DeCensi A, Puntoni M, Guerrieri A, et al: A randomized placebo-controlled phase III trial of low-dose tamoxifen for the prevention of recurrence in women with operated hormone-sensitive breast ductal or lobular carcinoma in situ. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 6, 2018.
7. Vicini F, Cecchini R, White J, et al: Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation versus partial breast irradiation for women with stage 0, I, or II breast cancer. 2018 San Antonio Breast Cancer Symposium. Abstract GS4-04. Presented December 6, 2018.
8. Correa C, Harris EE, Leonardia MC, et al: Accelerated partial breast irradiation: Executive summary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol 7:73-79, 2017.
9. Rutgers EJT, Donker M, Poncet C, et al: Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: 10-year follow-up results of the EORTC AMAROS trial. 2018 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 6, 2018.
10. Giulani A, McCall LM, Beitsch PD, et al: Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: The ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA 318:918-926, 2017.
11. Bidard FC, Jacot W, Dureau S, et al: Clinical utility of circulating tumor cells (CTC) count to choose between 1st line hormone therapy & chemotherapy in ER+ HER2– metastatic breast cancer: Results of the phase III STIC CTC trial. 2018 San Antonio Breast Cancer Symposium. Abstract GS3-07. Presented December 6, 2018.
12. Schmid P, Adams S, Rugo H, et al: Atezolizumab plus nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108-2121, 2018.
13. Emens LA, Loi S, Rugo HS, et al: Impassion130: Efficacy in immune biomarker subgroups from the global, randomized, double-blind, placebo-controlled phase III study of atezolizumab plus nab paclitaxel in patients with treatment-naive, locally advanced or metastatic triple negative breast cancer. 2018 San Antonio Breast Cancer Symposium. Abstract GS1-04. Presented December 5, 2018.