Chase Doyle

Treatment with anthracyclines was proven to be beneficial for patients with high-risk, HER2-negative, early-stage breast cancer, according to a joint analysis of the &ldquo;ABC&rdquo; trials presented at the 2016 ASCO Annual Meeting

The analysis, which included more than 4000 patients, demonstrated that docetaxel plus cyclophosphamide (TC) was significantly inferior to various taxane-plus-anthracycline-based (TaxAC) chemotherapy regimens.

&ldquo;Statistical noninferiority of the non-anthracycline regimen could not be demonstrated,&rdquo; said lead investigator Joanne Lorraine Blum, MD, PhD, medical oncologist with Texas Oncology at the Baylor-Sammons Cancer Center in Dallas. &ldquo;In terms of the study&rsquo;s primary endpoint, invasive disease-free survival, TC x 6 was significantly inferior to TaxAC.&rdquo;

National Surgical Adjuvant Breast and Bowel Project (NSABP) and US Oncology Research (USOR) collaborated with separate sponsors on 3 sequential clinical trials that randomized women with resected high-risk, early-stage breast cancer to receive TC or one of several standard TaxAC regimens. The researchers prospectively agreed to combine the efficacy data in an analysis that was prespecified in the third protocol (NSABP B-49). These are collectively referred to as the &ldquo;ABC Trials.&rdquo;

Researchers analyzed 4156 of the 4242 patients randomized in the ABC Trials. Patients with node-positive or high-risk node-negative breast cancer participated in the trials, which were designed to test non-inferiority of TC to TaxAC with respect to invasive disease-free survival (iDFS). A hazard ratio (HR) from a stratified Cox model of 1.18 or more was pre-defined as inferior. HRs above 1 favor TaxAC.

The TaxAC options included AC every 2 or 3 weeks followed by paclitaxel every week or every 2 weeks; all were compared to TC every 3 weeks for 6 cycles. Patients were stratified for parent trial, positives nodes (0, 1-3, 4-9, 10+), and hormonal status (negative, positive). Follow-up ranged from 2.2 years to 6.3 years in the separate studies.

Data cutoff for the interim analysis was October 31, 2015. The observed HR on the initial 334 events was 1.202, which exceeded the pre-specified threshold for futility (>1.18) and triggered consideration for early reporting.

The 4-year iDFS was 88.2% in the TC arm versus 90.7% for patients on TaxAC. At approximately 95% in both groups, researchers observed no difference in overall survival, Blum reported.

Exploratory subgroup analyses suggested that TaxAC provided minimal, if any, benefit in ER-positive/node-negative cohorts; a small benefit in ER-positive/1-3 positive nodes and ER-negative/node-negative cohorts; and a large benefit in ER-positive/&ge;4 positive nodes and ER-negative/node-positive cohorts.

There were more first iDFS events, both distant and local or regional, in the TC arm (n = 220) versus TaxAC arm (n = 179). However, said Blum, acute leukemia occurred as a first event in 5 of 2050 patients assigned to TaxAC versus none in the TC arm.

&ldquo;Additional follow-up and correlative studies to identify biomarkers of anthracycline benefit will be crucial for fully determining the utility of anthracyclines across the heterogeneous patient population,&rdquo; Dr. Blum concluded.

Tiffany A. Traina, MD, Clinical Director of the Breast Medicine Service at Memorial Sloan Kettering and Assistant Professor of Medicine at Weill Cornell Medicine, said, &ldquo;The overall trial results demonstrate that not only is TC not non-inferior to TaxAC in DFS, but TC x 6 is significantly inferior to the anthracycline and taxane-containing regimens in terms of DFS.&rdquo;

Despite the small percentage of first events, leukemia risk associated with TaxAC remains low, she added, and subset analyses should be interpreted with caution.

&ldquo;As of today, anthracycline and taxane-based adjuvant regimens are an appropriate choice for node-positive or high-risk, node-negative breast cancers. While not perfect, it&rsquo;s highly encouraging to see how well this entire study population performed,&rdquo; Traina concluded.

Prior to the findings from the ABC trial, the role for anthracyclines in patients with HER2-negative breast cancer had been hotly debated, according to Blum. Although subsets of early anthracycline trials suggested that only patients with HER2-positive tumors derived benefit from anthracyclines, these subset analyses were never conclusive.

Recent trials have shown that when taxanes are added to anthracyclines breast cancer mortality is reduced by more than a third compared with no chemotherapy. However, these benefits must be considered in the context of risk, said Blum, as anthracyclines are associated with a slight, but real, risk of cardiotoxicity and acute leukemia.

In addition, the sequential development of anthracyclines followed by taxanes has made evaluation of de-escalation of TaxAC regimens by removing anthracyclines challenging.

&ldquo;The pivotal study of TC x 4 versus AC x 4 demonstrated overall survival superiority for TC,&rdquo; said Blum. &ldquo;This established TC as an effective non-anthracyclines regimen appropriate for comparing with TaxAC regimens.&rdquo;

Blue JL, Flynn PJ, Yothers G, et al. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer.

Articles

Treatment with anthracyclines was proven to be beneficial for patients with high-risk, HER2-negative, early-stage breast cancer.

Use of Anthracyclines Plus Taxanes Found to be Beneficial in Early, HER2-Negative Breast Cancer

Phase III results of the KRISTINE trial demonstrated that patients with HER2-positive early breast cancer had a significantly higher pathological complete response (pCR) rate when they received the neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCH+P) versus trastuzumab emtansine (T-DM1) plus pertuzumab (T-DM1+P).

While the TCH+P regimen was also associated with a higher rate of breast conserving surgery, researchers reported that T-DM1+P had a notably better safety profile and that health-related quality of life and physical functioning were maintained longer.

&ldquo;Neoadjuvant TCH+P achieved a superior pCR rate compared with T-DM1+P and was associated with a higher breast-conserving-surgery rate,&rdquo; said Sara A. Hurvitz, MD, General Internal Medicine, Hematology & Oncology, UCLA Medical Center. &ldquo;However, neoadjuvant T-DM1+P had a more favorable safety profile, with lower incidence of grade 3 or greater adverse events, serious adverse events, and adverse events leading to treatment discontinuation.&rdquo;

T-DM1 and pertuzumab bind to different HER2 domains and have marked antitumor activity in HER2-positive breast cancer. KRISTINE, results of which were presented at the 2016 ASCO Annual Meeting, shows the first phase III data for a neoadjuvant regimen that omits standard chemotherapy for HER2-positive breast cancer.

From June 2014 to June 2015, researchers at 68 centers in 10 countries enrolled 444 patients with centrally confirmed HER2-positive breast cancer greater than 2 cm in size. Patients were randomly assigned to receive T-DM1+P or the TCH+P regimen. Both regimens were given every 3 weeks for 6 cycles. At the end of the first cycle, patients underwent a core needle biopsy of the tumor for biomarker endpoints.

After 6 cycles, patients received standard of care surgery, and after surgery, they went on to receive 12 more doses of HER2-directed therapy according to the arm they were in. Patients in the T-DM1+P arm who had significant residual disease at the time of the surgery were encouraged to receive standard chemotherapy before receiving a maintenance therapy regimen.

Baseline characteristics were well distributed to 2 treatment arms by age, world region, estrogen receptor (ER)/progesterone receptor (PR) status, and stage.

The pCR rate in the breast and lymph nodes was 56% in the TCH+P arm and 44% in the T-DM1+P arm. This 11% difference was statistically significant, said Hurvitz, favoring the TCH+P arm.

In patients with ER- and PR-negative breast cancer, TCH+P yielded a pCR of 73% in breast and lymph nodes compared with 54% in the T-DM1+P arm.

In hormone receptor (HR)positive breast cancer, the pCR was 44% in the TCH+P arm and 35% in the T-DM1+P arm, also favoring TCH+P. Over 60% of patients had HR-positive breast cancer, Hurvitz noted.

A preplanned, subgroup analysis showed that the benefits seen with TCH+P tended to favor all subgroups (age, world region, clinical stage at diagnosis and HR status). In addition, more women in the TCH+P underwent breast-conserving surgery (52.6% vs 41.7%, P = .0228).

In contrast, neoadjuvant T-DM1+P was associated with longer maintenance of patient-reported health-related quality of life and physical functioning, said Hurvitz. Neoadjuvant T-DM1+P also had a more favorable safety profile with a lower rate of grade 3/4 adverse events (AEs) (13% vs. 64%), serious AEs (5% vs. 29%), and AEs leading to treatment discontinuation (3% vs. 9%).

Cardiac event rates were unusual and were similar in the 2 treatment arms. Grade 3/4 AEs occurring in at least 3% of patients in either treatment arm included febrile neutropenia, neutropenia, diarrhea, and cytopenias, all of which were more common in the traditional chemotherapy arm compared with the T-DM1+P regimen.

Biomarker data and longer-term follow-up will be reported at a later date, said Hurvitz. In addition, there are several studies evaluating the use of T-DM1 in the early stage setting, including the KATHERINE and KAITLIN trials.

Hurvitz SA, Martin M, Symmans WF, et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). J Clin Oncol 34, 2016 (suppl; abstr 500).

Phase III results of the KRISTINE trial demonstrated that patients with HER2-positive early breast cancer had a significantly higher pathological complete response (pCR) rate when they received the neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCH+P) versus trastuzumab emtansine (T-DM1) plus pertuzumab (T-DM1+P). &nbsp;

KRISTINE Trial Demonstrates TCH+P Still Best Choice for HER2+ Breast Cancer

In patients with HER2-positive early breast cancer, data from a phase III trial has shown a significantly higher pathological complete response (pCR) rate with neoadjuvant docetaxel plus carboplatin plus trastuzumab plus pertuzumab (TCH+P) versus trastuzumab emtansine plus pertuzumab (T-DM1+P).

According to the results of the KRISTINE trial, the TCH+P regimen was also associated with a higher rate of breast conserving surgery. However, researchers reported that T-DM1+P had a notably better safety profile and that health-related quality of life and physical functioning were maintained longer.

&ldquo;Neoadjuvant TCH+P achieved a superior pCR rate compared with T-DM1+P and was associated with a higher breast-conserving-surgery rate,&rdquo; said Sara A. Hurvitz, MD, General Internal Medicine, Hematology & Oncology, UCLA Medical Center in Santa Monica, CA. &ldquo;However, neoadjuvant T-DM1+P had a more favorable safety profile, with lower incidence of grade 3 or greater adverse events, serious adverse events, and adverse events leading to treatment discontinuation.&rdquo;

As Dr. Hurvitz reported at the 2016 ASCO Annual Meeting, trastuzumab, emtansine, and pertuzumab bind different HER2 domains and have marked antitumor activity in HER2-positive breast cancer. KRISTINE presents the first phase III data for a neoadjuvant regimen that omits standard chemotherapy for HER2-positive breast cancer.

From June 2014 to June 2015, researchers at 68 centers in 10 countries enrolled 444 patients with centrally confirmed HER2-positive breast cancer greater than 2cm in size. Patients were randomly assigned to receive T-DM1+P or the TCH+P regimen. Both regimens were given every 3 weeks for 6 cycles. At the end of the first cycle, patients underwent a core needle biopsy of the tumor for biomarker endpoints.

After 6 cycles, patients received standard of care surgery, and after surgery, they went on to receive 12 more doses of HER2-directed therapy according to the arm they were in.

Patients in the T-DM1+P arm who had significant residual disease at the time of the surgery were encouraged to receive standard chemotherapy before receiving a maintenance therapy regimen.

As Dr. Hurvitz reported, the pCR rate in the breast and lymph nodes was 56% in the TCH+P arm and 44% in the T-DM1+P arm. This 11% difference was statistically significant, said Dr. Hurvitz, favoring the TCH+P arm.

In patients with ER- and PR-negative breast cancer, TCH+P yielded a pCR of 73% in breast and lymph nodes, compared to 54% in the T-DM1+P arm.

In hormone receptor (HR)positive breast cancer, the pCR was 44% in the TCH+P arm and 35% in the T-DM1+P arm, also favoring TCH+P. Over 60% of patients had HR-positive breast cancer, Dr. Hurvitz noted.

A preplanned, subgroup analysis showed that TCH+P tended to favor all subgroups (age, world region, clinical stage at diagnosis and HR status). In addition, more women in the TCH+P underwent breast conserving surgery (52.6% vs 41.7%,

In contrast, neoadjuvant T-DM1+P was associated with longer maintenance of patient-reported health-related quality of life and physical functioning, said Dr. Hurvitz. Neoadjuvant T-DM1+P also had a more favorable safety profile with a lower rate of grade 3/4 adverse events (AEs) (13% vs. 64%), serious AEs (5% vs. 29%), and AEs leading to treatment discontinuation (3% vs. 9%).

Biomarker data and longer-term follow-up will be reported at a later date, said Dr. Hurvitz. In addition, there are several studies evaluating the use of T-DM1 in the early stage setting, including the KATHERINE and KAITLIN trials.

Cardiac event rates were unusual and were similar in the 2 treatment arms. Grade 3/4 AEs occurring in at least 3% of patients in either treatment arm included febrile neutropenia, neutropenia, diarrhea, and cytopenias, all of which were more common in the traditional chemotherapy arm compared to the T-DM1+P regimen.

Hurvitz SA, Martin M, Symmans WF, et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE).

In patients with HER2-positive early breast cancer, data from a phase III trial has shown a significantly higher pathological complete response (pCR) rate with neoadjuvant docetaxel plus carboplatin plus trastuzumab plus pertuzumab versus trastuzumab emtansine plus pertuzumab.

Comparing Combination Treatments in HER2-Positive Early Breast Cancer

Interim analysis of a clinical trial of multiplex gene testing for inherited cancer risk suggests that fears of unnecessary surgery or adverse psychological effects associated with testing may be unwarranted.

According to data presented at the 2016 ASCO Annual Meeting, patients undergoing genetic testing for pathogenic mutations did not demonstrate increased rates of prophylactic surgeries, intrusive thoughts, or regrets. Patients who were positive for genetic mutations were also more likely to advise relatives to get tested, suggesting that they understood the implications of test results, the researchers reported.

&ldquo;After multiplex testing of diverse patients, few reported preventive surgery at 3 months,&rdquo; said Allison W. Kurian, MD, MSc, associate professor of Medicine and of Health Research and Policy at Stanford University School of Medicine, and director of the Stanford Women&rsquo;s Cancer Genetics Clinic. &ldquo;In addition, patients testing positive for a variant of uncertain significance (VUS) had no more distress, regret or uncertainty than negative patients.&rdquo;

As Dr. Kurian explained, the use of multiplex gene panels, which can simultaneously test between 15 and 40 genes, is on the rise, leading to a significant increase in the pathogenic detection rate of mutations in selected patients. However, this heightened sensitivity comes with the added cost of complexity.

&ldquo;Sequencing more genes increases the likelihood of finding VUS, which can be frustrating for both patients and clinicians,&rdquo; said Dr. Kurian. &ldquo;The key question here is, does multi-gene panel testing cause distress or inappropriate intervention?&rdquo;

Researchers in 3 cancer genetics clinics (LA County, University of South California, and Stanford University) conducted a prospective cohort study of a multi-gene panel, sequencing the following genes:

APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53

Patients were eligible for the study if they had no prior genetic testing, were 18 years or older, and had at least a 2.5% probability of carrying 1 of the mutations on the panel.

Participants were surveyed at entry, and then 3, 6, and 12 months after receiving their results. These surveys included a validated instrument, the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale, to measure distress.

Dr. Kurian and colleagues aim to enroll 2000 patients, with a planned interim analysis after 1000.

Of the 1000 participants (818 female), 11.6% tested positive for a pathogenic mutation, 51.9% were negative, and 36.5% had a VUS in any of the genes. With 38% non-Hispanic whites, 4.1% non-Hispanic blacks, 40% Hispanic, and 12.9% Asian, the patient population was also ethnically diverse, Dr. Kurian reported.

Analysis of post-testing surgical procedures showed that the rate of bilateral mastectomy at median follow up of 3 months was low (3%). In general, these were treatment mastectomies, said Dr. Kurian, with only 1 in the VUS category being reported for cancer prevention.

Researchers also observed low rates of prophylactic hysterectomy (1.5%) and oophorectomy (0.8%), with the majority of both types of operations being for cancer treatment.

Patients were then asked to report their experience in relation to genetic testing, grouped by the categories of positive, VUS, and negative. According to survey results, adverse psychological effects were minimal.

&ldquo;At least at this early stage, we don&rsquo;t see much evidence of harm in terms of high prophylactic surgery rates or intrusive thoughts or regret,&rdquo; said Dr. Kurian.

&ldquo;Most patients never or rarely had thoughts of cancer affecting daily activities, never regretted testing, and wanted to know all results, even those that doctors do not fully understand,&rdquo; she added.

Results of the validated MICRA questionnaire were divided into 3 components: distress, uncertainty, and positive experiences.

&ldquo;As could be expected, patients who tested positive had slightly higher distress scores compared to the negative and VUS groups. However, uncertainty was not so different, and there were only slightly lower positive experiences of testing among patients who test positive for a mutation,&rdquo; said Dr. Kurian.

In addition, scores of VUS patients did not differ significantly from those of negative patients for any MICRA components.

&ldquo;It appears that the VUS patients were really behaving more like the negative patients and not like the positive patients in this setting,&rdquo; Dr. Kurian reported.

Finally, researchers asked patients whether they notified their relatives about their results and whether those relatives went on to have a genetic evaluation or testing.

Interim analysis showed that patients who had a positive pathogenic mutation encouraged relatives to have genetic testing (81.8%) significantly more than VUS (38.2%) or negative patients (37.8%,

&ldquo;We think that notification and testing of relatives at this early stage appears relatively appropriate,&rdquo; said Dr. Kurian. &ldquo;Patients who have a pathogenic mutation were more likely to tell their relatives to test, which is what we&rsquo;d hope to see.&rdquo;

That being said, with a median of only 3.3 months, follow-up time remains short at this stage of the study.

&ldquo;It will be interesting to see if rates of prophylactic surgery, distress, or regret rise as the trial progresses,&rdquo; said Dr. Kurian. &ldquo;And what will happen if these VUS are reclassified?&rdquo;

Researchers expect enrollment of 2000 patients to be completed by the end of the year.

Kurian AW, Idos G, Culver J, et al. Safety of multiplex gene testing for inherited cancer risk: Interim analysis of a clinical trial.

Chase Doyle | Authors

Articles

Use of Anthracyclines Plus Taxanes Found to be Beneficial in Early, HER2-Negative Breast Cancer

KRISTINE Trial Demonstrates TCH+P Still Best Choice for HER2+ Breast Cancer

Comparing Combination Treatments in HER2-Positive Early Breast Cancer

Minimal Harm Associated with Multiplex Gene Testing for Inherited Cancer Risk