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San Antonio Breast Cancer Symposium 2017
The San Antonio Breast Cancer Symposium (SABCS), held December 5–9, 2017, drew an attendance of approximately 7,500 medical professionals. We review key sessions on dose intensification, cyclin-dependent kinase 4/6 inhibition, new trial data of combination and adjuvant therapies, acupuncture for aromatase inhibitor arthralgia, and ovarian suppression to potentially preserve fertility in young women undergoing cancer treatment.
Increasing the Dose Intensity of Adjuvant Chemotherapy: An EBCTCG Meta-Analysis
Breast cancer recurrence and death are reduced by increasing dose intensity of adjuvant chemotherapy, according to a meta-analysis of 25 early breast cancer trials. Dr. Gray presented the findings of the study during an SABCS press briefing.
Speaking for the Early Breast Cancer Trialists’ Collaborate Group (EBCTCG), he noted that much of contemporary adjuvant chemotherapy is given on conventional schedules every three weeks and is associated with a mortality reduction of about one-third. Cytokinetic modeling, however, suggests that greater chemotherapy dose density, achieved by shortening the intervals between courses or by using sequential as opposed to concurrent treatment schedules, may enhance efficacy. Dose density can be increased in three ways: higher drug doses in each cycle; reduced intervals between treatment cycles; and sequential dosing (e.g., an anthracycline alone followed by a taxane alone).
The difficulty associated with the first strategy, Dr. Gray said, is that doubling a dose does not double the benefit and will likely increase toxicities. “The cleaner way of intensifying the dose is simply to give the drugs in a shorter interval,” he said. While eight courses of treatment given every three weeks is typical, giving them every two weeks is feasible. In addition, restarting drug therapy sooner can potentially “knock the tumor cells before they can grow back.”
The EBCTCG meta-analysis included seven trials (n = 10,004) evaluating the dosing of the same drugs every two weeks versus every three weeks and five trials (n = 5,508) evaluating treatment with some differences in chemotherapy every two weeks versus every three weeks. The analysis also evaluated sequential therapy every three weeks in five trials of the same drugs (n = 9,644) and in one trial with some differences in drugs (n = 1,384). Finally, the EBCTCG meta-analysis included six trials of sequential (every two weeks) versus concurrent (every three weeks) treatment with some differences in the drugs used (n = 6,532). The primary outcomes were recurrence and breast cancer mortality.
Dr. Gray reported that increasing the dose intensity of chemotherapy reduced the recurrence and death from breast cancer by about 15%. Pooled analysis (n = 34,122) showed an overall relative risk reduction in recurrence of 15% (32.0% versus 28.4%; P < 0.00001) and a mortality reduction of 13% (22.2% versus 19.5%; P < 0.00001).
Reductions in recurrence with dose-intense chemotherapy were similar in estrogen receptor-positive (ER+) and ER– disease and did not differ significantly by any other tumor or patient characteristic. There were no increases in death without recurrence when the dose-intense and standard arms were compared (overall or during chemotherapy).
“So whichever way the trials achieved dose intensification, they seem to be finding benefits and fewer recurrences. This is quite remarkable how consistent all these different approaches were,” Dr. Gray said. He recommended more trials like this addressing “bread-and-butter” questions, such as whether eight courses are better than six courses.
MONALEESA-7: Ribociclib Improved Progression-Free Survival for Pre- and Perimenopausal Women With Hormone Receptor-Positive Advanced Breast Cancer
In postmenopausal women with de novo and/or recurrent hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer, adding ribociclib (Kisqali, Novartis) to letrozole significantly prolonged progression-free survival (PFS) compared with letrozole alone, according to MONALEESA-7 findings.
Younger women with advanced breast cancer have a distinct tumor biology, experience more aggressive disease, and are more likely to die from their cancer than older women, Dr. Tripathy noted in an SABCS press conference. It was estimated, he said, that in 2017 in the U.S. about 19% of invasive breast cancers would be diagnosed in women 49 years of age or younger, with higher rates (42%) in the Asia-Pacific region. While endocrine therapy with ovarian suppression is the recommended first-line treatment for premenopausal women with HR+, HER2– advanced breast cancer, resistance and disease progression ultimately occur.
Investigators enrolled 672 patients in MONALESSA-7, the first phase 3 trial investigating cyclin-dependent kinase (CDK) 4/6 inhibitor-based regimens as a front-line treatment specifically for premenopausal women with advanced breast cancer. The patients were randomized to ribociclib in combination with either tamoxifen or a nonsteroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) and goserelin (n = 335) or to placebo in combination with the same oral hormonal therapy options and goserelin (n = 337). Ribociclib is an orally available CDK inhibitor targeting the cyclin D1/CDK4 and cyclin D3/CDK6 cell cycle pathway. The primary endpoint was investigator-assessed PFS.
The median age of patients in MONALEESA-7 was about 44 years; approximately 58% of the women were Caucasian and about 30% were Asian. Dr. Tripathy reported that the MONALEESA-7 primary endpoint was met, with median PFS significantly improved in the ribociclib arm at 23.8 months compared with 13.0 months in the placebo arm (hazard ratio [HR], 0.553; P = 0.0000000983). Among women receiving tamoxifen as the partner drug to ribociclib, median PFS was 22.1 months in the ribociclib arm and 11.0 months in the placebo arm (HR, 0.585). In those receiving an NSAI with ribociclib, median PFS was 27.5 months versus 13.8 months for placebo (HR, 0.569). Subgroup analysis revealed PFS benefits for ribociclib across all subgroups.
Among the secondary endpoints, overall response rate was 40.9% in the ribociclib plus tamoxifen/NSAI arm and 29.7% in the placebo plus tamoxifen/NSAI arm (P = 0.00098). Among those women with measurable disease, the respective rates were 50.9% and 36.4% (P = 0.000317). The clinical benefit rate in this latter group was 79.9% for those receiving ribociclib and 67.3% for those receiving placebo (P = 0.00034).
While neutropenia was higher in the ribociclib arm (76.0% versus 8.0% in the placebo arm), it was associated with fever and infection in only 2.0% of ribociclib patients and in 1.0% of placebo patients.
SABCS Co-Director and press conference moderator Virginia Kaklamani, MD, leader of the breast cancer program at The University of Texas Health Science Center at San Antonio, asked Dr. Tripathy if he felt that oncologists are replacing chemotherapy with CDK4/6 inhibitors in the metastatic setting. He responded, “I think so. There has been a trend to use hormonal therapy even before these drugs came on the scene. But we have very few trials. Most patients who are watched carefully can do just as well with hormonal therapy in the front line. The new biological agents, especially this class of drugs, do represent, for an even greater population of patients, the ideal first-line treatment.” He commented further that he tends to use aromatase inhibitors among possible endocrine partners because “they are associated with slightly improved outcomes, and their toxicity profiles may be a little more favorable. They can cause more symptoms than tamoxifen, so it’s good to have it available as an option.”
Evaluating the Safety and Efficacy of Pembrolizumab and Trastuzumab in Patients With Trastuzumab-Resistant HER2-Positive Metastatic Breast Cancer: Results From the Phase 1b/2 PANACEA Study
The PANACEA study met its primary endpoint among women with metastatic, human epidermal growth factor receptor 2-positive (HER2+) breast cancer resistant to trastuzumab (Herceptin, Genentech) who received pembrolizumab (Keytruda, Merck) with trastuzumab. No responses were observed in patients who were programmed death ligand-1 (PD-L1) negative.
Dr. Loi noted at an SABCS press briefing that HER2+ breast cancer has high levels of T-cell infiltration. Tumor-infiltrating lymphocytes (TILs) are associated with improved prognosis and response to trastuzumab and chemotherapy. In addition, trastuzumab has been shown to have immune-mediated mechanisms of action. Preclinical studies have suggested immune-mediated mechanisms of trastuzumab resistance that can be overcome with checkpoint inhibition combinations.
PANACEA, a phase 1b/2 clinical trial, enrolled 58 women with advanced breast cancer that had progressed on prior trastuzumab-based treatment. Tumors were centrally assessed for HER2 positivity, PD-L1 status, and the number of TILs. The phase 1b dose-escalation portion of the trial found no dose-limiting toxicities for the anti-PD-1 agent pembrolizumab. The phase 2 study included 40 PD-L1-positive and 12 PD-L1-negative patients. All received intravenous pembrolizumab 200 mg every three weeks in combination with standard trastuzumab doses for 24 months or until disease progression. The primary objectives were efficacy and safety for the combination among patients with PD-L1-expressing tumors. Rejecting the null hypothesis required six or more objective responses in the phase 2 portion. An exploratory analysis of efficacy according to baseline stromal TIL (sTIL) levels was also planned.
Mean age was 49 years in the PD-L1-positive patients and 56.5 years in the PD-L1-negative patients. Immune-related adverse events led to discontinuations in four patients (6.9%), with thyroid dysfunction and pneumonitis most common. No cardiac events were reported.
In the PD-L1-positive intent-to-treat population, the objective response rate was 15.2% (one complete response and five partial responses), and the disease control rate was 24.0%. The median duration of disease control was 11.1 months, and the median duration of response was 3.5 months. Mean duration of response was 10.0 months. Five patients (10.8%) continue with no progression, Dr. Loi said. Twelve-month progression-free survival was 13.0% in PD-L1-positive patients and 0% in PD-L1-negative patients (P = 0.07). She noted that 12-month overall survival was 65.0% in the PD-L1-positive group and 12.0% in the PD-L1-negative group (P = 0.0006). “PD-L1 status is prognostic, and also contains all the responders,” Dr. Loi commented.
Regarding the exploratory endpoint, Dr. Loi noted, “We observed that the median level of TIL infiltration in the metastatic lesions was 1.0%, which was 20 times less than what we observed in primary HER2+ breast cancers. However, we did note a significantly higher TIL level in the PD-L1-positive cohort and also significantly higher TIL levels in patients who achieved an objective response or disease control. So higher TIL levels are associated with an increased chance of response.”
Dr. Loi also said that in seeking a potential predictive marker for response, the PANACEA team found that with sTILs of 5% or higher compared with sTILs lower than 5%, the objective response rate was 39% versus 5%. Disease control rates were 47% versus 5% at the same cut-offs.
“For responders, the pembrolizumab and trastuzumab combination offers durable control without chemotherapy,” she concluded. She observed that metastatic HER2+ disease in the heavily pretreated setting is poorly immunogenic (the majority of patients had low TILs in metastatic lesions).
The Synergism or Long Duration (SOLD) Trial: A Randomized Phase 3 Study of Adjuvant Trastuzumab for Nine Weeks Versus One Year Combined With Adjuvant Taxane-Anthracycline Chemotherapy for Early HER2-Positive Breast Cancer
While noninferiority of nine-week administration of trastuzumab (Herceptin, Genentech) plus docetaxel versus chemotherapy and one-year duration of adjuvant trastuzumab could not be demonstrated for disease-free survival (DFS), docetaxel dosing with trastuzumab warrants further study in early human epidermal growth factor receptor 2-positive (HER2+) breast cancer, according to Dr. Joensuu.
Based on several lines of evidence, concomitant administration of trastuzumab with a taxane improves trastuzumab efficacy and might be synergistic. In addition, continuing trastuzumab after combined trastuzumab and taxane might not markedly add to efficacy, he suggested. While chemotherapy plus trastuzumab for one year is the current standard of care, small trials have shown similar DFS and overall survival in patients receiving either nine weeks or 12 months of trastuzumab. One year of treatment with trastuzumab is lengthy, expensive, and sometimes associated with adverse cardiac events. Congestive heart failure was reported in fewer than 3% of patients in the pivotal trials, but risk is probably greater in elderly patients, Dr. Joensuu said.
The Synergism or Long Duration (SOLD) trial investigators randomly assigned 2,176 patients (median age, 56 years) with early-stage HER2+ breast cancer 1:1 to a nine-week trastuzumab arm or a 12-month trastuzumab arm. Included patients had histologically confirmed HER2+ disease that was node-positive, or node-negative with a size larger than 5 mm (if 6–10 mm, histological grade 2 or 3), and had left ventricular ejection fractions of 50% or greater.
Patients in both arms received three cycles of docetaxel (80 mg/m2 or 100 mg/m2) and trastuzumab three times a week, followed by three cycles of chemotherapy. While patients in the nine-week arm received no further treatment, those in the 12-month arm received trastuzumab every three weeks for 14 cycles. Women with estrogen receptor-positive cancer received guideline-recommended endocrine treatment and radiation therapy as per institutional practice.
The five-year survival estimates placed DFS at 90.5% in the 12-month treatment arm and 88.0% in the nine-week treatment arm (hazard ratio [HR], 1.39; 90% confidence interval [CI], 1.12–1.72). The overall survival five-year estimate was 95.9% in the 12-month arm and 94.7% in the nine-week arm (HR, 1.36; 95% CI, 0.98–1.89), and distant DFS was 94.2% and 93.2%, respectively (HR, 1.24; 90% CI, 0.93–1.65).
A prespecified DFS subgroup analysis showed benefit for the nine-week regimen over the 12-month regimen among patients receiving a docetaxel dose of 100 mg/m2 (92.2% for nine weeks versus 87.8% for 12 months; HR, 0.71; 90% CI, 0.44–1.14), but showed advantage for 12-month treatment among those receiving docetaxel at 80 mg/m2 (91.3% for 12 months versus 86.8% for nine weeks; HR, 1.66; 90% CI, 1.30–2.11).
Cardiac toxicity was higher in the 12-month treatment group compared with the nine-week group (3.9% versus 2.0%; P = 0.012). Congestive heart failure was reported in 1.9% of the nine-week group and in 3.3% in the 12-month group (P = 0.046).
“Chemotherapy plus one year of anti-HER2 therapy should remain the standard,” Dr. Joensuu concluded. He noted, however, that there was not much difference between groups in distant DFS and overall survival and that further study of docetaxel/trastuzumab dosing is warranted.
Acupuncture Reduced Joint Pain Caused By Aromatase Inhibitor Treatment in a Randomized, Phase 3 Clinical Trial
Among postmenopausal women with early-stage breast cancer receiving treatment with an aromatase inhibitor, acupuncture treatment significantly reduced joint pain, according to results of the randomized, phase 3 SWOG S1200 trial.
“Aromatase inhibitors are among the most common and most effective treatments for postmenopausal women diagnosed with hormone receptor-positive [HR+] breast cancer; however, many patients suffer from side effects that cause them to miss treatments or stop treatment altogether,” Dr. Hershman said. “We need to identify strategies to control these side effects, the most common of which is debilitating joint pain and stiffness.” She noted that several small studies have suggested that acupuncture may be beneficial for aromatase inhibitor-associated arthralgia.
The trial, conducted at 11 centers, included 226 early-stage HR+ breast cancer patients (median age, 60.7 years), all of whom had pain starting or increasing after initiation of aromatase inhibitor therapy. Investigators randomized 59 patients to sham acupuncture with needles inserted into nonacupoints and 110 patients to true acupuncture (Chinese medicine point prescriptions). Fifty-seven patients were assigned to wait-list control (no treatment). Patients receiving true acupuncture or sham acupuncture had twice-weekly sessions for six weeks followed by one session per week for six more weeks. Pain measures included the Brief Pain Inventory–Short Form (BPI), a self-administered 14-item questionnaire with a 0-to-10 scale with higher scores indicating more pain and pain impact on functioning. The primary outcome was mean worst BPI pain score at six weeks.
The mean BPI worst pain for the true acupuncture arm was 0.92 points lower than the mean BPI worst pain for the sham acupuncture arm (P = 0.01) and 0.96 points lower than the mean BPI worst pain for the wait-list control arm (P = 0.01). In addition, the proportion of patients who had a reduction of two or more points in worst pain was significantly greater in the true acupuncture arm than in the sham acupuncture and wait-list control arms (58%, 33%, and 31%, respectively; P < 0.009; P < 0.004). The same pattern of significant benefit for the true acupuncture group versus sham and wait-list groups persisted in BPI stiffness evaluated with the Western Ontario and McMaster Universities Osteoarthritis Index for hips/knees and the Modified Score for the Assessment and Quantification of Chronic Rheumatic Affections of the Hands.
Dr. Hershman noted that while the acupuncture intervention was completed by 12 weeks, the pain score improvements remained statistically significant at the 24-week assessment.
Grade 1 bruising was more common with true acupuncture than with sham acupuncture (47% versus 25%; P = 0.01). Otherwise adverse events were generally absent or minimal for both.
“We have shown consistently, with multiple measures assessing pain and stiffness, that true acupuncture generated better outcomes than either control group in a large multicenter randomized controlled trial,” Dr. Hershman said.
Phase 3 EMBRACA Trial: Talazoparib Prolonged Progression-Free Survival in Patients With Advanced, BRCA-Mutated Breast Cancer
“In EMBRACA, talazoparib [investigational, Pfizer] demonstrated superior clinical benefit in all subsets of patients, regardless of receptor subtype (HR [hormone receptor]-positive or triple-negative breast cancer), number of prior lines of chemotherapy, BRCA mutation type, and central nervous system metastasis,” Dr. Litton said in an SABCS press briefing. She noted that talazoparib is a dual mechanism inhibitor of the poly (ADP-ribose) polymerase (PARP) enzyme that also traps PARP on DNA, preventing DNA damage repair and leading to the death of BRCA1/2-mutated cells. Promising results with talazoparib have been reported in early phase trials.
EMBRACA is an open-label, randomized, phase 3 trial comparing the efficacy and safety of 1 mg talazoparib daily with standard, single-agent, physician’s choice of therapy (PCT) in patients with advanced breast cancer and a germline BRCA1/2 mutation. PCT generally consisted of capecitabine, eribulin (Halaven, Eisai, Inc.), gemcitabine, or vinorelbine. Investigators randomly assigned patients (2:1) to talazoparib (n = 287) or PCT (n = 144). Progression-free survival (PFS), assessed by blinded independent central review, was the primary outcome measure, with secondary objectives of overall survival (OS), overall response rate (ORR), clinical benefit rate at 24 weeks (CBR24), and safety.
Median PFS was 8.6 months for patients in the talazoparib arm versus 5.6 months for those in the PCT arm (P < 0.0001). Patients in the talazoparib arm were 45.8% less likely to have disease progression compared with those in the PCT arm. Improvements in ORR and CBR24 also favored talazoparib significantly. Complete responses were observed in 12 patients receiving talazoparib and none in the PCT group. Time to clinical deterioration was 24.3 months for talazoparib patients and 6.3 months for those receiving PCT. While overall survival data are not yet mature (51% of projected events), the hazard ratio is currently 0.76 (95% confidence interval, 0.54–1.06; P = 0.105), a trend favoring talazoparib.
Grade 3–4 hematologic adverse events were reported in 55% of patients receiving talazoparib and 39% receiving PCT. Grade 3–4 gastrointestinal and skin/subcutaneous tissue disorder rates were lower for the talazoparib group. Overall, grade 3–4 serious adverse event rates were similar for the two groups (approximately 25%). Rates of adverse event-attributable deaths were 2.1% and 3.2%, respectively, for the talazoparib and PCT arms. “Talazoparib was generally well tolerated, with minimal nonhematologic toxicity and few adverse events resulting in treatment discontinuation,” Dr. Litton said. Quality-of-life assessments showed that patients receiving talazoparib had a significant delay in the time to deterioration in health compared with patients in the PCT arm.
Phase 3 Trial of Additional Two Years Versus Additional Five Years of Anastrozole After Initial Adjuvant Endocrine Therapy: The ABCSG-16 Trial
In the ABCSG-16 trial, adding five years of anastrozole to standard five-year adjuvant endocrine therapy (tamoxifen, aromatase inhibitor [AI] sequence) did not improve disease-free survival (DFS) compared with an additional two years of anastrozole, Dr. Gnant said at an SABCS press briefing.
Long-term risk of relapse in hormone receptor-positive (HR+) breast cancer is significant, and more than half of disease relapses occur after the first five years of follow-up. While extended adjuvant therapy with AIs after initial tamoxifen has been demonstrated to improve the DFS of postmenopausal patients with HR+ breast cancer, the optimal duration of extended AI therapy is unknown. Moreover, it remains unclear whether patients after AI treatment in the first five years benefit similarly from extended adjuvant AI therapy as patients do after tamoxifen. It is important to establish how long the treatment should be given, Dr. Gnant said, “because this treatment leads to prolonged side effects and impacts quality of life.”
ABCSG-16 investigators enrolled 3,484 postmenopausal women with HR+ early-stage breast cancer in 71 Austrian centers and randomized them to receive either two years or five years of extended adjuvant therapy. All had undergone an initial five years of adjuvant endocrine treatment (either tamoxifen or other regimens containing AIs). Median patient age was 64 years. Eighty percent of women had breast-conserving surgery, and 29% had additional neoadjuvant chemotherapy. Tumor size was smaller than 2 cm in 72% of patients. Treatment in the first five years had been tamoxifen only in 51%.
After a median follow-up of 106.2 months, DFS was 71.1% in the two-year arm and 70.3% in the five-year arm (hazard ratio [HR], 1.007; 95% confidence interval [CI], 0.87–1.16; P = 0.925). The secondary endpoint of overall survival (OS) was 85.3% in the two-year arm and 84.9% in the five-year arm (HR, 1.007; 95% CI, 0.82–1.23; P = 0.947). Time to contralateral breast cancer and time to second primary cancer were similar for both groups.
The difference in fracture rates in the five-year and two-year groups (6.3% versus 4.7%, respectively) nearly achieved statistical significance (HR, 1.353; 95% CI, 1.00–1.84; P = 0.053).
“There is no benefit of continuing/escalating endocrine treatment beyond seven years,” Dr. Gnant concluded. “Extension of anastrozole treatment to five additional years leads to increased side effects including fractures and should be avoided.”
Temporary Ovarian Suppression With Hormone Analogue May Preserve Fertility During Breast Cancer Chemotherapy
Treatment with a gonadotropin-releasing hormone analogue (GnRHa) could safely and effectively protect ovarian function and potentially preserve fertility in premenopausal women receiving chemotherapy for early-stage breast cancer, according to a meta-analysis of five randomized clinical trials.
“Fertility preservation and pregnancy-related issues are high-priority areas of concern for young women with breast cancer,” Dr. Lambertini noted. Premature ovarian insufficiency (POI) is a common side effect of chemotherapy in premenopausal patients, he added, with substantial negative impacts on their quality of life. Oocyte/embryo cryopreservation are standard strategies for fertility preservation, but they do not prevent the risk of chemotherapy-induced POI. While temporary ovarian suppression with GnRHa during chemotherapy has been studied in randomized controlled trials as a strategy to preserve ovarian function and potential fertility, data are mixed and its role remains controversial.
Dr. Lambertini and colleagues conducted a systematic review and meta-analysis of five clinical trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) with GnRHa use during chemotherapy, with ovarian function and fertility preservation as the efficacy outcome and with survival as the safety outcome. The analysis included 436 women receiving GnRHa and 437 women as controls (median age, approximately 38.5 years).
Dr. Lambertini reported that the rate of POI was 14.1% in the GnRHa group and 30.9% in the control group (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.26–0.57; P < 0.001). While the secondary endpoint of one-year amenorrhea was similar for the groups (36.8% for GnRHa versus 40.4% for controls), two-year amenorrhea significantly favored the GnRHa group (18.2% versus 30.0%) (OR, 0.51; 95% CI, 0.31–0.85; P = 0.009). Post-treatment pregnancy rates were higher in the GnRHa group (10.3% versus 5.5%; P = 0.030). There was also a trend favoring OS for the GnRHa group (hazard ratio, 0.67; 95% CI, 0.42–1.06; P = 0.083). “This suggests that administering GnRHa during chemotherapy can be considered safe in breast cancer patients,” he said.
“This strategy should be considered as an option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal early breast cancer patients undergoing neoadjuvant chemotherapy,” he said.