Joanne L. Blum M.D.

Blum, J. L., N. Robert, J. Andersen, A. Favret, P. Ward, C. Osborne and J. Pippen (2018). “Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy in Early-Stage Invasive Breast Cancer.” J Clin Oncol 36(4): 428-429.

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Although we agree with the decision of the ASCO Guideline Panel members to update the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer1 on the basis of the published results of the MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial, we take exception with two issues. One is the language used in most of the detailed recommendations in the update, which state that physicians “should” or “should not” use specific tests in specific situations. We believe that the use of directive language, such as should and should not, goes beyond the concept of recommended guidelines and becomes a directive to clinicians. We note that recommendation 1.2.1 includes language that states that physicians “may” use the 70-gene signature assay and does not use the more directive should or should not language. Second, we agree that the 70-gene assay may provide some utility for decision making for patients with breast cancer with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2–negative, lymph node–positive disease with one to three positive lymph nodes. However, we note that this recommendation is based on a small prospective data set of 731 women with lymph node–positive disease with one to three positive lymph nodes and high clinical and low genomic risk who were randomly assigned to receive chemotherapy or not. Although the entire high clinical and low genomic risk group included 1,550 women randomly assigned to receive chemotherapy or not, this group included both patients with positive and patients with negative lymph nodes. The outcome data provided for the entire group as noted in Figure 2 and Table 3 of the report included one half of the patients who had lymph node–negative disease. Moreover, follow-up for this study is still short at only 5 years, and the results may change with later follow-up. (Excerpt from text.)

Blum, J. L., N. Robert, J. Andersen, A. Favret, P. Ward, C. Osborne and J. Pippen (2017). “Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy in Early-Stage Invasive Breast Cancer.” J Clin Oncol: Jco2017753756.

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TO THE EDITOR: Although we agree with the decision of the ASCO Guideline Panel members to update the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer1 on the basis of the published results of the MINDACT (Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy) trial,2 we take exception with two issues. One is the language used in most of the detailed recommendations in the update, which state that physicians “should” or “should not” use specific tests in specific situations. We believe that the use of directive language, such as should and should not, goes beyond the concept of recommended guidelines and becomes a directive to clinicians. We note that recommendation 1.2.1 includes language that states that physicians “may” use the 70-gene signature assay and does not use the more directive should or should not language.

Blum, J. L., P. J. Flynn, G. Yothers, L. Asmar, C. E. Geyer, Jr., S. A. Jacobs, N. J. Robert, J. O. Hopkins, J. A. O’Shaughnessy, C. T. Dang, H. L. Gomez, L. Fehrenbacher, S. J. Vukelja, A. P. Lyss, D. Paul, A. M. Brufsky, J. H. Jeong, L. H. Colangelo, S. M. Swain, E. P. Mamounas, S. E. Jones and N. Wolmark (2017). “Anthracyclines in early breast cancer: The abc trials-usor 06-090, nsabp b-46-i/usor 07132, and nsabp b-49 (nrg oncology).” J Clin Oncol 35(23): 2647-2655.

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Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.

Ghouadni, A., S. Delaloge, P. Lardelli, C. Kahatt, T. Byrski, J. L. Blum, A. Goncalves, M. Campone, A. Nieto, V. Alfaro, M. Cullell-Young and J. Lubinski (2017). “Higher antitumor activity of trabectedin in germline brca2 carriers with advanced breast cancer as compared to brca1 carriers: A subset analysis of a dedicated phase ii trial.” Breast 34: 18-23.

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Specific alkylators may allow synthetic lethality among patients with germline BRCA1/2-mutations related cancers. The tetrahydroisoquinolone trabectedin administered at 1.3 mg/m2 as a 3-h intravenous infusion every 3 weeks showed activity in patients with pretreated metastatic breast cancer (MBC) and BRCA germline mutations, but mainly in BRCA2 carriers. Data from a phase II study were retrospectively analyzed to compare the efficacy and safety of this trabectedin dose and schedule in pretreated MBC patients bearing germline BRCA1/2 mutations. The primary efficacy endpoint was the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST) by independent expert review. Duration of response (DR) and progression-free survival (PFS) were secondary efficacy endpoints. Safety was evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Data from 26 BRCA1-mutated and 13 BRCA2-mutated patients were analyzed. 69% of BRCA1-mutated cancers were triple-negative vs. 31% of BRCA2-mutated ones. 77% of BRCA1 and 31% of BRCA2 carriers were platinum-pretreated. The ORR in BRCA2-mutated patients was higher than in BRCA1-mutated patients (33.3% vs. 9.1%). DR ranged for 1.4-6.8 months in BRCA2-mutated patients and for 1.5-1.7 months in BRCA1-mutated patients. More BRCA2-mutated patients had disease stabilization for >/=4 months (25.0% vs. 9.1%) and their median PFS was longer (4.7 vs. 2.5 months). Trabectedin was well tolerated in both patient subtypes. In conclusion, trabectedin showed higher antitumor activity in relapsed MBC patients with germline BRCA2 mutations than in those with BRCA1 mutations.

Baselga, J., S. M. Morales, A. Awada, J. L. Blum, A. R. Tan, M. Ewertz, J. Cortes, B. Moy, K. J. Ruddy, T. Haddad, E. M. Ciruelos, P. Vuylsteke, S. Ebbinghaus, E. Im, L. Eaton, K. Pathiraja, C. Gause, D. Mauro, M. B. Jones and H. S. Rugo (2017). “A phase ii study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer.” Breast Cancer Res Treat 163(3): 535-544.

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PURPOSE: Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%). METHODS: This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] x 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd x 5 days/week. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS was 21.4 weeks for ridaforolimus 30 mg qd x 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy. CONCLUSIONS: The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.