Roundup of High-Impact Studies in Early Breast Cancer

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Clinicians interested in breast cancer who logged into the ASCO20 Virtual Scientific Program were greeted with an abundance of high-impact presentations. The ASCO Post has reported on several studies in depth elsewhere, but here we offer our readers a roundup of several important studies in early breast cancer.

Confirmatory MINDACT Update

Long-term analysis of the phase III MINDACT trial, with a median follow-up of 8.7 years, confirmed that the 70-gene signature MammaPrint assay can identify patients with breast cancer who may safely forgo adjuvant chemotherapy.1 It also showed the “excellent prognosis and low rates of events” in all groups, except women deemed at high risk by both clinical and genomic features, reported Fatima Cardoso, MD, of the Champalimaud Clinical Center/Champalimaud Foundation, Lisbon.

Fatima Cardoso, MD

Fatima Cardoso, MD

Distant metastasis–free survival was 94.7% for the group at clinically low/genomically low risk but dropped to 85.9% for the group at highest risk. “The primary endpoint continues to be met in chemotherapy-untreated women at clinically high/genomically low risk, confirming MINDACT as a positive de-escalation study,” she stated.

Of note, for the 749 women deemed at high clinical risk but low genomic risk, adjuvant chemotherapy provided just a small gain (2.6%) in distant metastasis–free survival compared with the 748 patients who did not receive chemotherapy (92.0% vs 89.4%). However, in premenopausal women, the difference was larger (5%) and possibly clinically relevant, according to Dr. Cardoso. “This effect may be related to chemotherapy-induced ovarian function suppression,” she noted. “Although cautious interpretation is needed, the analysis suggests that in women younger than age 50 at clinically high/genomically low risk, tamoxifen alone may not be optimal treatment.”

Outcomes Similar for Neoadjuvant Anastrozole and Fulvestrant

No clear winner emerged in the comparison between anastrozole and fulvestrant as neoadjuvant therapy in early hormone receptor–positive breast cancer in the ALTERNATE trial.2 Neoadjuvant endocrine therapy facilitates breast-conservation surgery. In such patients, the modified preoperative endocrine prognostic index (PEPI) score of 0 (pT1–2 pN0 Ki67 < 2.7% or pathologic complete response) is associated with a low risk of recurrence without adjuvant chemotherapy.

The ALTERNATE trial is assessing whether fulvestrant alone or with anastrozole increases the rate of endocrine-sensitive disease (the number of patients with a modified PEPI score of 0 divided by the number of patients starting neoadjuvant therapy). It is also asking whether the 5-year recurrence rate for patients receiving anastrozole alone with a modified PEPI score of 0 is at least 95% (those data will be reported at a later date).

Of 1,299 patients, 73% were considered candidates for breast-conserving surgery and were randomly assigned to 6 months of neoadjuvant fulvestrant alone, anastrozole alone, or both. Patients with Ki67 greater than 10% at week 4 or 12 were recommended to switch to chemotherapy. Those with a modified PEPI score of 0 at surgery continued their assigned endocrine therapy for 1.5 years followed by anastrozole for a total of 5 years of endocrine therapy. The primary endpoint of the neoadjuvant phase was the rate of endocrine-sensitive disease.

The rate of endocrine-sensitive disease was 22.7% with fulvestrant, 18.6% with anastrozole, and 20.5% with anastrozole plus fulvestrant. No significant difference in these rates was found between anastrozole and fulvestrant (P = .15) or anastrozole vs anastrozole/fulvestrant (P = .55), according to Cynthia X. Ma, MD, PhD, of Washington University, St. Louis.

Cynthia X. Ma, MD, PhD

Cynthia X. Ma, MD, PhD

Among the 825 patients with Ki67 less than 10% at week 4 who completed neoadjuvant therapy and surgery, the rates of breast-conserving surgery were 68.1%, 70.3%, and 69.9%, ­respectively.

“Neither fulvestrant nor fulvestrant plus anastrozole significantly improved the rate of endocrine-sensitive disease compared with anastrozole alone,” Dr. Ma said. Recurrence-free survival data are pending.

Negative Results for KAITLIN Trial

The phase III KAITLIN trial failed to meet its primary endpoint, as replacing adjuvant taxane and trastuzumab with ado-trastuzumab emtansine (T-DM1) did not result in a significant improvement in invasive disease–free survival in the node-positive or intent-to-treat population.3 However, encouragingly, this rate was around 94% at 3 years in both arms, “which is notable in this high-risk population,” said Nadia Harbeck, MD, of the University of Munich.

“Adjuvant trastuzumab plus pertuzumab and chemotherapy remains a standard of care for patients with high-risk, HER2-positive, early breast cancer,” Dr. Harbeck stated.

Nadia Harbeck, MD

Nadia Harbeck, MD

KAITLIN is a randomized, open-label study that enrolled 1,846 patients with HER2-positive hormone receptor–negative tumors > 2.0 cm and either node-positive or node-negative disease. Within 9 weeks of surgery, patients were randomly assigned to 3 to 4 cycles of anthracycline-based chemotherapy followed by 18 cycles of T-DM1 at 3.6 mg/kg plus pertuzumab at 420 mg every 3 weeks (AC-KP) or a taxane for 3 to 4 cycles plus concurrent trastuzumab at 6 mg/kg and pertuzumab at 420 mg every 3 weeks (AC-THP). Adjuvant radiotherapy and/or endocrine therapy were given after four cycles of HER2-targeted therapy.

The co-primary endpoint was invasive disease–free survival in the node-positive and intent-to-treat populations.

Invasive disease–free survival at 3 years was 94.1% with AC-THP and 92.8% with AC-KP in the node-positive population and 94.2% and 93.1%, respectively, in the intent-to-treat population. The incidence of grade ≥ 3 adverse events and serious adverse events was similar, but more patients receiving AC-KP than AC-THP discontinued T-DM1 or trastuzumab because of adverse events. On the other hand, AC-KP was associated with a lower risk of deterioration in global health status and quality of life.

3-Year TRAIN-2 Follow-up: Neoadjuvant Anthracyclines Not Necessary

The phase III TRAIN-2 study compared the efficacy and safety of an anthracycline-containing neoadjuvant regimen with an anthracycline-free regimen of the same duration, both including dual HER2 blockade, in patients with stage II or III breast cancer.4 Equally high pathologic complete response rates, the primary endpoint, were achieved with regimens that contained vs did not contain anthracyclines (67% vs 68%; P = .95), as reported previously.5

Pathologic complete response is an established surrogate endpoint in neoadjuvant trials, but follow-up data with survival endpoints are required to confirm benefit. These data showing 3-year survival confirmed the initial conclusion that anthracyclines do not improve efficacy and are associated with clinically relevant toxicity, said Anna van der Voort, MD, of the Netherlands Cancer Institute in Amsterdam.

Anna van der Voort, MD

Anna van der Voort, MD

“A neoadjuvant carboplatin/taxane-based regimen with dual HER2 blockade can be considered in all patients with stage II or III breast cancer, regardless of hormone receptor and nodal status,” she said.

The 438 patients were randomly assigned to receive either three cycles of fluorouracil, epirubicin, and cyclophosphamide followed by six cycles of paclitaxel and carboplatin, plus trastuzumab and pertuzumab (FECT-PTC); or nine cycles of paclitaxel and carboplatin followed by trastuzumab and pertuzumab (PTC). Patients completed 1 year of trastuzumab, radiotherapy, and endocrine therapy as indicated.

After a median follow-up of 48.8 months, the 3-year event-free survival estimates were 92.7% with FECT-PTC plus pertuzumab and 93.6% for PTC plus pertuzumab, and the 3-year overall survival rate was 97.7% vs 98.2%, respectively. These results were consistent, irrespective of hormone receptor and nodal status.

Although some oncologists believe anthracyclines are important in higher-risk patients, Dr. van der Voort said they found no evidence to support that higher-risk patients require anthracyclines.

Anthracyclines did add toxicity, however, including meaningful declines in left-ventricular ejection fraction (9% vs 3%) and more febrile neutropenia (10% vs 1%). Two patients who received FECT-PTC plus pertuzumab also developed acute leukemia. 

DISCLOSURE: Dr. Cardoso has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Healthcare, Genentech, GlaxoSmithKline, MacroGenics, Medscape, Merck Sharp & Dohme, Merus, Mundipharma, Mylan, Novartis, Pfizer, Pierre Fabre, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seattle Genetics, and Teva, and has received travel funds from AstraZeneca, Pfizer, and Roche. Dr. Ma has served as a consultant or advisor to Agendia, AstraZeneca, Lilly, Myriad Genetics, Novartis, Pfizer, Seattle Genetics, and Tempus; has received institutional research funding from Eisai, Pfizer, and Puma; and has been reimbursed for travel, accommodations, or other expenses by Agendia, Lilly, and Pfizer. Dr. Harbeck holds stock or other ownership interests in the West German Study Group; has received honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Roche; has served as a consultant or advisor to Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Genomic Health, Lilly, Merck Sharp & Dohme, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, and Seattle Genetics; and has received institutional research funding from Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Roche/Genetics. Dr. van der Voort reported no conflicts of interest.


1. Cardoso F, van’t Veer L, Poncet C, et al: MINDACT: Long-term results of the large prospective trial testing the 70-gene signature MammaPrint as guidance for adjuvant chemotherapy in breast cancer patients. ASCO20 Virtual Scientific Program. Abstract 506.

2. Ma CX, Suman VJ, Leitch AM, et al: ALTERNATE: Neoadjuvant endocrine treatment approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer in postmenopausal women: Alliance A011106. ASCO20 Virtual Scientific Program. Abstract 504.

3. Harbeck N, Im SA, Barrios CH, et al: Primary analysis of KAITLIN: A phase III study of trastuzumab emtansine + pertuzumab vs trastuzumab + pertuzumab + taxane, after anthracyclines as adjuvant therapy for high-risk HER2-positive early breast cancer. ASCO20 Virtual Scientific Meeting. Abstract 500.

4. van der Voort A, van Ramshorst MS, van Werkhoven EK, et al: Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2-blockade for HER2-positive breast cancer (TRAIN-2): A randomized phase III trial. ASCO20 Virtual Scientific Program. Abstract 501.

5. van Ramshorst MS, van der Voort A, van Werkhoven ED, et al: Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase III trial. Lancet Oncol 19:1630-1640, 2018.