REPORTERS FOR The ASCO Post captured the following summaries of noteworthy studies presented at the 2018 San Antonio Breast Cancer Symposium.
In HER2-Negative Metastatic Disease, CTCs Frequently HER2-Positive
ALMOST HALF of all patients with HER2-negative metastatic breast cancer have circulating tumor cells (CTCs) that are HER2-positive. This discordance is not a function of sampling at two different time points, but it happens even when the two assays are done simultaneously, researchers at Northwestern University, Chicago, reported at the meeting.1
“Discordance occurs simultaneously and frequently, and it occurs both early in the treatment course and after treatment,” said Ami N. Shah, MD, of Northwestern University Feinberg School of Medicine. She said the study describes a new CTC-defined HER2-positive subgroup of patients who might benefit from anti-HER2 therapy. In a subgroup of 18 patients with discordance treated with anti-HER2 therapy combined with chemotherapy or endocrine therapy, 44% had a clinical response, she noted.
“Discordance [between metastatic tumor and circulating tumor cells] occurs simultaneously and frequently, and it occurs both early in the treatment course and after treatment.”— Ami N. Shah, MD
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Dr. Shah and colleagues retrospectively analyzed data from 98 patients with serial evaluation of CTCs and circulating tumor DNA. They found that among patients deemed HER2-negative by standard immunohistochemistry and/or fluorescence in situ hybridization criteria of the metastatic tumor, 47% had at least 1 HER2-positive CTC detected on at least 1 analysis; 12% had detectable CTCs, all of which were HER2-negative, and 41% had no CTCs detected. Of those with HER2-positive CTCs, three-quarters were detected on the initial sample, with a median of 11.5 HER2-positive CTCs at initial detection.
As for the time frame of HER2 discordance, 48% occurred when tissue and CTC collection occurred “at the same time,” she said— ie, within 8 weeks of each other. “That was surprising,” Dr. Shah commented, explaining that HER2 positivity in these cases was not a result of the disease evolving over time.
“This suggests it is not temporal discordance, but likely some true discordance we are detecting. Maybe something is different about cells that have the ability to circulate.... What if those are the cells that can form new metastases?” If so, she said, perhaps HER2-targeted therapy might be able to reduce the CTC fraction and delay the time to metastases.
Adjuvant Trastuzumab: 6 Months Still the Standard
THE RANDOMIZED noninferiority French PHARE trial of 3,384 patients evaluated whether a shorter course of trastuzumab (6 months) might yield benefit that was comparable to the standard 12 months of treatment. In the final analysis of PHARE, presented in San Antonio by Xavier Pivot, MD, PhD, of the Paul Strauss Cancer Center, Strasbourg, PHARE failed to show that 6 months is noninferior (hazard ratio [HR] = 1.08), based on preservation of the 1.15 margin for noninferiority.2
Xavier Pivot, MD, PhD
“PHARE was not successful in demonstrating that 6 months is noninferior to 12 months of trastuzumab,” Dr. Pivot reported. “This was driven by the excess of events occurring within the first 2 years of completing trastuzumab. Beyond 2 years, relapses were not different between the two arms.”
At 7.5 years’ median follow-up, the proportion of patients with disease-free survival events was 20.4% after 12 months vs 21.2% after 6 months of treatment. These included, for 12 vs 6 months, respectively, local recurrences in 2.1% and 2.5%, regional recurrences in 1.0% and 1.1%, distant recurrences in 9.6% and 11.1%, contralateral breast cancers in 1.6% and 2.0%, second primaries in 4.6% and 3.6%, and death in 1.4% and 1.1%.
“Interestingly, the Persephone trial, reported at the 2018 ASCO Annual Meeting,3 had a similar design and similar hazard ratio (1.07) but an opposite conclusion,” Dr. Pivot added, explaining that this was related to the different margin of noninferiority (1.29).
Myelosuppression Reduction With Trilaciclib in Metastatic Triple-Negative Disease
ADDING THE cyclin D kinase (CDK) 4/6 inhibitor trilaciclib to chemotherapy with gemcitabine/carboplatin reduced the incidence of major adverse hematologic events in patients with metastatic triple-negative breast cancer, allowing for longer exposure to chemotherapy compared with gemcitabine/carboplatin alone, according to preliminary results of a randomized phase II trial.4 Adding 1 or 2 doses of trilaciclib per cycle seemed to lengthen progression-free survival and improve tumor response rates compared to chemotherapy alone.
For the study, major adverse hematologic events were defined as a composite measure that included all-cause hospitalizations, dose reductions, febrile neutropenia, prolonged severe neutropenia, and red blood cell and platelet transfusions. The rate of major adverse hematologic events was 13% with 1 dose of trilaciclib per cycle and 9% with 2 doses per cycle compared with 19% for patients treated with gemcitabine/carboplatin alone (P = .0181 for each dose level of trilaciclib plus chemotherapy vs chemotherapy alone). In addition, all-cause hospitalizations, prolonged severe neutropenia, and red blood cell transfusions were significantly reduced in both trilaciclib groups.
Trilaciclib is being developed to reduce the myelosuppressive effects of chemotherapy and preserve immune system function rather than to directly target tumor proliferation. The study included 98 evaluable patients with metastatic triple-negative breast cancer, randomly assigned to standard gemcitabine/carboplatin with or without trilaciclib.
With 1 dose of trilaciclib per cycle, chemotherapy could be given for a median of 20 weeks, and with 2 doses of trilaciclib per cycle, for a median of 19 weeks. By contrast, gemcitabine/carboplatin alone could be given for a median of 14.4 weeks. The number and type of grade 3 or 4 treatment-emergent adverse events were similar between the 2 arms, with the most frequent events being those associated with cytotoxic chemotherapy.
Joyce A. O’Shaughnessy, MD
“Trilaciclib prevented or delayed clinically significant major adverse hematologic events. It was these major adverse hematologic events—prolonged neutropenia, dose reductions, platelet transfusions, red blood cell transfusions—that seem to be impacted,” said lead author Joyce A. O’Shaughnessy, MD, Chair of Breast Cancer Research at Baylor-Sammons Cancer Center, Dallas. Three other randomized phase II trials are currently evaluating trilaciclib in addition to chemotherapy.
Antihypertensive Agents May Reduce Cardiotoxicity Risk in HER2-Positive Disease
USE OF prophylactic antihypertensive medication appears to abrogate the risk of cardiotoxicity to some extent in patients with early HER2-positive breast cancer treated with trastuzumab and anthracycline-based chemotherapy but does not seem to help patients treated with trastuzumab and non–anthracycline-based regimens, according to the results of a randomized trial.5
The trial did not meet the primary endpoint of cardiotoxicity in the overall study population, but use of a beta-blocker or angiotensin-converting enzyme inhibitor reduced cardiotoxicity by about 50% in patients when trastuzumab was added to anthracycline-based adjuvant chemotherapy. There was no reduction in cardiotoxicity in patients getting trastuzumab with no anthracycline-based chemotherapy.
Pamela Munster, MD
“The primary endpoint was similar for all cohorts,” reported lead author Pamela Munster, MD, Director of the Early Phase Clinical Trials Unit at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. There was no significant difference between carvedilol and placebo or lisinopril and placebo for cardiotoxicity-free survival, she noted.
“The addition of lisinopril or carvedilol should be considered in patients with HER2-positive breast cancer treated with trastuzumab and anthracyclines,” she said.
The community-based trial involved 127 practices across the United States, with a total of 468 patients. Patients had early HER2-positive breast cancer and were slated for treatment with trastuzumab for 1 year. They received adjuvant or neoadjuvant chemotherapy, had left-ventricular ejection fraction (LVEF) ≥ 50%, systolic blood pressure ≥ 90 mm Hg, and pulse ≥ 60 beats per minute. They were randomly assigned to lisinopril at 10 mg, carvedilol at 10 mg, or placebo and further stratified by anthracycline use. Of 468 patients, 189 were treated with anthracycline-based chemotherapy plus trastuzumab.
The primary endpoint was defined as an absolute 10% decrease in LVEF from baseline or a 5% absolute decrease in LVEF below 50%. Speaking from the audience, Steven E. Vogl, MD, a frequent contributor to The ASCO Post, questioned the validity of LVEF as an endpoint reflective of cardiotoxicity that actually affects patients.
Steven E. Vogl, MD
“These results did not address the key issues for patients. You have shown that you have fewer decreases in LVEF so you can give more trastuzumab, but did these interventions prevent dyspnea, heart failure—something that bothered the patient?” Dr. Vogl asked Dr. Munster.
She replied that this was a community-based trial and at the time of study initiation this endpoint was the most robust and reproducible endpoint across multiple centers and an endpoint considered in many other studies at that time to assess long-term cardiac health.
The primary analysis found that the rates of cardiotoxicity were 30% for lisinopril, 29% for carvedilol, and 32% for placebo. A nonsignificant trend suggested that both drugs improved cardiotoxicity-free survival compared with placebo. A preplanned subgroup analysis, however, showed a significant advantage for cardioprophylaxis with either agent vs placebo in patients treated with anthracycline-based chemotherapy plus trastuzumab: a 51% reduction in the cardiotoxicity-free survival hazard with carvedilol (P = .009) and a 47% reduction with lisinopril (P = .015).
Cardioprophylaxis was also preventive against treatment disruption with trastuzumab, which occurred in 26.3% of placebo recipients as compared with 17.3% with lisinopril and 15.4% with carvedilol (P = .01). Adverse events related to both antihypertensive agents were similar to their established safety profiles.
Durvalumab May Amplify Response to Olaparib in BRCA-Positive Metastatic Disease
ADDING THE checkpoint inhibitor durvalumab to olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), appeared to prolong response to olaparib, according to an interim analysis of a cohort of patients with BRCA-mutated breast cancer enrolled in the open-label phase II MEDIOLA trial (a basket trial of various cancers with BRCA mutations).6 This is a preliminary study with a small number of patients, and longer follow-up is needed to determine the duration of response.
Susan M. Domchek, MD
“The idea is that if you can get a response with olaparib, it’s possible that durvalumab will lead to a longer duration of response because olaparib generates DNA damage, so there may be some antigens expressed. Then, the durvalumab will produce [something akin to] autovaccination, producing a prolonged response,” said lead author of this poster, Susan M. Domchek, MD, Director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia.6
MEDIOLA enrolled a cohort of 34 patients with HER2-negative, locally advanced or metastatic breast cancer and germline BRCA mutation. Patients were treated with prior anthracycline and/or taxane therapy but no prior PARP inhibitor or immunotherapy. Enrolled patients received olaparib at 300 mg twice daily for a 4-week run-in period, then went on to olaparib at 300 mg twice daily plus durvalumab intravenously every 4 weeks. Treatment with the combination continued until progressive disease.
The median age was 45 years. Fifty percent had a documented BRCA1 mutation, and 50% had a BRCA2 mutation. About 43% were hormone receptor–positive; 57% had triple-negative breast cancer. Approximately 30% had received no prior chemotherapy, 37% had 1 prior line of chemotherapy, and 33% had 2 prior lines.
Among 30 evaluable patients, the disease control rate (the primary endpoint) was 80% at 12 weeks, which improved upon the prespecified target of 75%, Dr. Domchek noted. At 28 weeks, the overall response rate was 63%, the median duration of response was 9.2 months, and the median progression-free survival was 8.2 months. The median duration of response of 9.2 months compares favorably to the median of 6.4 months reported with olaparib monotherapy in the OlympiAD study7 in patients with BRCA-mutated metastatic breast cancer, Dr. Domchek noted.
The researchers plan to analyze predictors of response—including programmed cell death ligand 1 expression—as the trial progresses. The most common grade ≥ 3 adverse events related to olaparib were anemia (12%) and neutropenia (6%), whereas pancreatitis (6%) was the most common adverse event related to durvalumab.
Venetoclax Highly Active in Estrogen Receptor–Positive, BCL2-Positive Disease
THE ADDITION of the B-cell lymphoma (BCL)2 inhibitor venetoclax to endocrine therapy seemed to improve responses in patients with metastatic breast cancer that was estrogen receptor–positive and BCL2-positive, in a small phase Ib study.8 The investigators used a higher dose of venetoclax than is used in hematologic malignancies, and the combination was tolerable. This is the first study to evaluate venetoclax in a solid tumor, noted lead author Geoffrey J. Lindeman, MD, of the Walter and Eliza Hall Institute of Medical Research, Melbourne.
Geoffrey J. Lindeman, MD
Based on the promising activity in this phase Ib trial, a phase II study is currently underway. It is enrolling patients with estrogen receptor–positive disease who have disease progression on CDK4/6 inhibitors and is randomly assigning them to receive fulvestrant alone or fulvestrant with venetoclax at 800 mg.
For 33 evaluable patients treated with venetoclax plus tamoxifen, median progression-free survival was 36 weeks overall; it was 36 weeks in the dose-escalation phase and 48 weeks in the dose-expansion phase. Median progression-free survival was 23 weeks in a group of patients treated with venetoclax at less than 800 mg vs 51 weeks in those treated with 800 mg (the maximum planned dose in the study).
In the dose-escalation phase, the overall response rate was 27% and the clinical benefit rate was 67%. No patient had a complete response, and the median duration of response was 61 weeks. In the dose-expansion phase, the overall response rate was 61% and the clinical benefit rate was 72% (1 complete response). The median duration of response was 39 weeks.
Among 24 patients treated at the maximum 800-mg dose, the overall response rate was 54% and clinical benefit rate was 75% (1 complete response and 12 partial responses). The median duration of response was 42 weeks. A total of 8 patients on the 800-mg cohort remained on study treatment.
Dr. Lindeman explained that about 80% of estrogen receptor–positive breast cancers are BCL2-positive. “We found in this study that about 70% of tumors remain BCL2-positive in patients who undergo a biopsy of their metastases,” he said, and preclinical evidence suggests that venetoclax is synergistic with endocrine therapy.
No patient discontinued therapy due to adverse events. The major side effects with venetoclax were on-target effects. Lymphopenia occurred in 100% at venetoclax < 800 mg and in 83% at the 800-mg dose (most grade ≤ 2). Neutropenia occurred in 56% at the lower doses and in 79% at the upper dose (most grade ≤ 2). No infections occurred at the lower dose, but infections were seen in 38% at the upper dose, although most were grade ≤ 2, and no grade 4 infections were seen. Two-thirds of patients had nausea (grade ≤ 2), which was manageable with metoclopramide.
Androgen/Estrogen Receptor Coexpression and Treatment Outcome
THE ANDROGEN and estrogen receptors are frequently coexpressed, and this seems to portend for better outcomes with palbociclib, a small study indicated.9
Chrystal A. Landry, MD
Previous studies have revealed preliminary efficacy signals for androgen receptor blockade in metastatic breast cancer, predominantly in patients with androgen receptor (AR)-positive, triple-negative breast cancer. Chrystal A. Landry, MD, of Northwell Cancer Institute in New Hyde Park, New York, and colleagues sought to further evaluate AR expression and its significance in patients with estrogen receptor–positive metastatic breast cancer treated with palbociclib early in their metastatic treatment course. The study’s senior author was Amy Tiersten, MD, of Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai, New York.
They found that 59% of patients expressed the AR (> 0% staining), with 55% having > 10% expression and 41% having > 20% expression. Patients with AR-positive disease experienced significantly fewer adverse events (HR = 0.26; P = .01), with a median event-free survival of 18.8 months, compared to 5.4 months for patients with only estrogen receptor expression.
“There is preliminary evidence that intact phosphorylated retinoblastoma protein is associated with AR expression. This may represent a mechanism by which cell-cycle inhibition with palbociclib may be particularly effective in these patients,” Dr. Landry suggested.
“The relatively common expression of the androgen receptor in estrogen receptor–positive metastatic breast cancer may provide a rationale for continuing CDK4/6 inhibitors in combination with AR targeting in these patients,” she said. ■
DISCLOSURE: Drs. Shah, Pivot, Munster, and Landry reported no conflicts of interest. Dr. O’Shaughnessy’s study received support from GI Therapeutics; she has consulted for Celgene, Pfizer, AstraZeneca, and Novartis; and she is a member of the medical advisory board for Theranostics Health Inc. Dr. Domchek has received honoraria from AstraZeneca, Clovis, and Bristol-Myers Squibb and institutional research funding from AstraZeneca, Clovis, and PharmaMar. Dr. Lindeman is an employee of the Walter and Eliza Hall Institute, which receives royalties and milestone payments related to venetoclax from AbbVie and Genentech; he has received remuneration related to venetoclax from the Walter and Eliza Hall Institute and research support from AbbVie.
REFERENCES
1. Shah AN, et al: HER2-negative metastatic breast cancer with HER2-positive circulating tumor cells. 2018 San Antonio Breast Cancer Symposium. Abstract P3-01-08. Presented December 6, 2018.
2. Pivot X, et al: PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer. 2018 San Antonio Breast Cancer Symposium. Abstract GS2-07. Presented December 5, 2018.
3. Earl HM, et al: Persephone: 6 versus 12 months of adjuvant trastuzumab in patients with HER2 positive early breast cancer. 2018 ASCO Annual Meeting. Abstract 506. Presented June 4, 2018.
4. O’Shaughnessy J, et al: Trilaciclib, a CDK4/6 inhibitor, dosed with gemcitabine, carboplatin in metastatic triple-negative breast cancer patients. 2018 San Antonio Breast Cancer Symposium. Abstract PD1-01. Presented December 5, 2018.
5. Munster P, et al: A randomized, community-based trial of an angiotensin-converting enzyme inhibitor, lisinopril, or beta-blocker, carvedilol, for the prevention of cardiotoxicity in patents with early-stage HER2-positive breast cancer receiving adjuvant trastuzumab. 2018 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 7, 2018.
6. Domchek SM, et al: An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA). 2018 San Antonio Breast Cancer Symposium. Abstract PD5-04. Presented December 6, 2018.
7. Robson M, et al: Olaparib for metastatic breast cancer in patients with germline BRCA mutation. N Engl J Med 377:523-533, 2017.
8. Lindeman GJ, et al: A phase 1b dose-escalation and expansion study of the BCL2 inhibitor venetoclax combined with tamoxifen in ER and BCL2-positive metastatic breast cancer. Cancer Discov. December 5, 2018 (early release online).
9. Landry CA, et al: The significance of androgen receptor co-expression in ER+ metastatic breast cancer patients treated with palbociclib. 2018 San Antonio Breast Cancer Symposium. Abstract P5-11-07. Presented December 7, 2018.
