Shannon Puhalla

Randomized Phase II Adjuvant Trial of Dose-Dense Docetaxel Before or After Doxorubicin Plus Cyclophosphamide in Axillary Node-Positive Breast Cancer

PURPOSEnAn anthracycline-based combination followed by, or combined with, a taxane is the sequence used in most adjuvant chemotherapy regimens. We hypothesized that administering the taxane before the anthracycline combination would be associated with fewer dose reductions and delays than the reverse sequence. To test this hypothesis, a randomized phase II multicenter adjuvant chemotherapy trial was performed.nnnPATIENTS AND METHODSnFifty-six patients with axillary node-positive, nonmetastatic breast cancer were randomly assigned either to group A (docetaxel [DOC] 75 mg/m(2) intravenously [IV] every 14 days for four cycles followed by doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) [AC] IV every 14 days for four cycles); or to group B (AC followed by DOC) at the identical doses and schedule. Pegfilgrastim 6 mg subcutaneous injection was administered 1 day after the chemotherapy in all treatment cycles. The primary objective was to administer DOC without dose reductions or delays before or after AC and calculate the relative dose intensity (RDI) of DOC and AC.nnnRESULTSnThe majority of toxicities were grade 0 to 2 irrespective of sequence. The RDI for DOC was 0.96 and 0.82, respectively, in groups A (DOC followed by AC) and B (AC followed by DOC), with more frequent dose reductions occurring in group B (46% v 18%). The RDI for AC was 0.95 and 0.98 in groups A and B, respectively.nnnCONCLUSIONnThe administration of DOC before AC results in fewer DOC dose reductions and a higher RDI than the reverse sequence. Larger trials evaluating the sequence of DOC before anthracyclines are justified.

Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole

ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR. Mutation rate was 31.3% (5/16) (n=3; de novo, n=2; acquired). D538G was the most frequent mutation (n=3), followed by Y537N and Y537S (n=2). One patient showed multiple ESR1 mutations. Mutations were enriched during therapy. Progression-free survival (PFS) and overall survival (OS) were similar in patients with and without mutation detected at any given time during treatment. However, PFS was significantly shorter in patients with ESR1 mutation at initial blood draw (3.3 versus 9.0 months, P-value=0.038). In conclusion, ESR1 mutation prevalence is consistent with recent studies in hormone-refractory breast cancer. Further, treatment with palbociclib and letrozole does not prevent selection of ESR1 mutations in later lines of therapy. Larger studies are warranted to validate these findings.

Magee Equation 3 predicts pathologic response to neoadjuvant systemic chemotherapy in estrogen receptor positive, HER2 negative|[sol]|equivocal breast tumors

Magee Equations were derived as an inexpensive, rapid alternative to Oncotype DX. The Magee Equation 3 utilizes immunohistochemical and FISH data for estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 for its calculation (24.30812+ERIHC × (−0.02177)+PRIHC × (−0.02884)+(0 for HER2 negative, 1.46495 for equivocal, 12.75525 for HER2 positive)+Ki-67 × 0.18649). We hypothesize that Magee Equation 3 scores from pre-therapy core biopsy can predict response to neoadjuvant systemic chemotherapy. A prospectively-maintained database of patients who received neoadjuvant systemic therapy from 2010 to 2014 at a single institution was retrospectively reviewed. Pathologic complete response was defined as absence of invasive tumor in the breast and regional lymph nodes. Of the 614 cases, tumors with missing immunohistochemical results and those that were ER negative or HER2 positive were excluded. This resulted in 237 ER positive, HER2 negative/equivocal tumors that formed the basis of this study. Magee Equation 3 scores were divided into 3 categories similar to Oncotype DX, ie, 0 to <18 (low), 18 to <31 (intermediate), and 31 or higher (high) scores. The pathologic complete response rate for low, intermediate and high Magee Equation 3 scores was 0%, 4%, and 36%, respectively. Patients with high Magee Equation 3 scores were 13 times more likely to achieve pathologic complete response compared to those with Magee Equation 3 scores less than 31 (95% CI 5.09–32.87, P<0.0001). For patients that did not achieve pathologic complete response, high Magee Equation 3 correlated with higher recurrence rate, with the majority occurring in patients with positive lymph nodes in the resection specimen. Magee Equation 3 score ≥31 predicts pathologic complete response in the neoadjuvant setting and for tumor recurrence, when pathologic complete response is not achieved. These results show the utility of Magee Equation 3 in predicting patients who will benefit from chemotherapy but warrant prospective multi-institutional validation.

Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V).

135 Background: Veliparib (V) (ABT-888) is an oral, potent inhibitor of PARP 1/2. PARP inhibitors have preclinical and clinical efficacy in BRCA+ malignancies. There are genotypic and phenotypic similarities between BRCA+ cancers, serous ovarian cancer and basal-like breast cancer and we postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose -limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed V in 2 cohorts of patients, BRCA+ and BRCA-wt (consisting of serous ovarian cancer and triple-negative breast cancer (TNBC).nnnMETHODSnA 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28 day cycle. BRCA+ and BRCA-wt patients were enrolled in 2 separate cohorts with 2 separate escalations.nnnRESULTSn98 (70 BRCA+ and 28 BRCA-wt) pts have been enrolled. The maximum administered dose (MAD) was 500mg BID and the MTD/RP2D is 400mg BID for both cohorts. 59 BRCA+ pts and 24 BRCA-wt pts (21 TNBC and 3 ovary) were evaluable for response. ORR was defined as CR+PR and clinical benefit rate (CBR) as CR+PR+SD > 6 months. Results are summarized in the table.nnnCONCLUSIONSnThere is evidence of anti-tumor activity with V comparable to that of other PARP inhibitors in the BRCA+ population. There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly TNBC, BRCA-wt population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance.nnnCLINICAL TRIAL INFORMATIONnNCT00892736. [Table: see text].

A case of late-onset gemcitabine lung toxicity.

Gemcitabine is a chemotherapeutic agent used for the treatment of a number of malignancies. Although its major dose-limiting side effect is myelosuppression, many pulmonary toxicities have been described with its use. Severe pulmonary toxicity is rare, but symptoms tend to be rapid in onset and potentially deadly. The average time from initiation of chemotherapy to onset of symptoms is less than two months. The most effective therapy is steroid administration, the efficacy of which has been variable. In this report, we describe a unique case of gemcitabine pulmonary toxicity in a patient who did not experience symptoms of pulmonary dysfunction until after 1 year of treatment. Her symptoms did not improve rapidly with steroids, nor did she rapidly decompensate as has been frequently described. To our knowledge, this is one of the first reported descriptions of late-onset gemcitabine lung toxicity.

Should We Embrace or Ablate Our Urge to (Ovarian) Suppress

The quest to define optimal endocrine therapy for premenopausal women with early-stage breast cancer began more than 50 years ago but is still unfulfilled. Multiple strategies have emerged, including tamoxifen, ovarian function suppression (OFS) by surgery, luteinizing hormone–releasing hormone agonist or radiation, and combination strategies such as tamoxifen plus OFS or aromatase inhibitor plus OFS. An added confounder is that these strategies have frequently been assessed in the context of adjuvant chemotherapy, which is commonly used in premenopausal women and may have indirect endocrine effects because of chemotherapy-induced menopause. This complex landscape was reviewed in a 2011 American Society of Clinical Oncology (ASCO) endorsement of the 2010 Cancer Care Ontario guideline recommending against the routine use of OFS in addition to tamoxifen or chemotherapy and a 2014 ASCO guideline endorsing consideration of 10 years of tamoxifen for these young women with hormone-responsive disease. Against this backdrop, in the article that accompanies this editorial, Tevaarwerk et al report the final results of a phase III Eastern Cooperative Oncology Group trial (E-3193, INT-0142) in which 345 premenopausal women with lymph node–negative, hormone receptor–positive breast cancer measuring 3 cm were randomly assigned from 1994-1997 to receive 5 years of tamoxifen alone or 5 years of tamoxifen plus OFS; no chemotherapy was permitted. With a median follow-up of almost 10 years, there were no significant differences in the primary end points of disease-free survival (DFS; 87.9% v 89.7% P .62) or overall survival (95.2% v 97.6%; P .67). Secondary end points included toxicity and several patient-reported outcomes (PROs) including menopausal symptoms, sexual function, and health-related quality of life. These results suggest that tamoxifen plus OFS leads to increased toxicity, more menopausal symptoms, and reduced sexual function, peaking around year 3 and then diminishing over time. The strengths of this study include the importance of the question, the clean design that enabled the testing of hormone therapies in the absence of chemotherapy, the focus on hormone-responsive tumors, the balance between the arms, the long follow-up, and the assessment of PROs. The major limitation is, of course, that the study’s early closure as a result of poor accrual left it vastly underpowered for its primary end points; this trial fell victim to the 1997 report of National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, which recommended the use of chemotherapy in addition to tamoxifen for women with axillary lymph node–negative, hormoneresponsive breast cancer, especially women younger than 50 years of age. However, E-3193 was a success in its collection of detailed PROs, and it is noteworthy that it met the prespecified target accrual for these secondary end points. Given the exceptional outcomes for patients enrolled onto this trial, which had greater than 95% overall survival in the absence of chemotherapy, such patient-reported data are valuable contributions to the discussion between physicians and patients about the risks and benefits of individual therapies. Several crucial questions remain. Given the statistical limitations of this trial, might the combination of OFS plus tamoxifen actually be better than tamoxifen? What about the combination of OFS plus an aromatase inhibitor, given the efficacy of aromatase inhibitors in postmenopausal hormone receptor–positive breast cancer? Three large trials are helping to address these two questions: ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12), SOFT (Suppression of Ovarian Function Trial), and TEXT (Tamoxifen and Exemestane Trial). A lingering concern is how we can integrate the results of all of these trials that use 3 to 5 years of adjuvant endocrine therapy with the findings of the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTom (Adjuvant Tamoxifen—To Offer More?) trials, which support the use of 10 years of tamoxifen. In the SOFT trial, 3,066 premenopausal women with hormoneresponsive breast cancer were randomly assigned to 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS; (neo)adjuvant chemotherapy was permitted as long as patients remained premenopausal at its completion. In the TEXT trial, 2,672 premenopausal patients with hormone-responsive breast cancer were randomly assigned to receive 5 years of tamoxifen plus OFS or exemestane plus OFS; endocrine therapy was started concurrently with chemotherapy if chemotherapy was planned. Because of lower than expected event rates, the statistical plans for these two trials were revised some years ago to enable a joint analysis of 4,690 women receiving tamoxifen plus OFS versus exemestane plus OFS. In contrast to E-3193, 42% of these women were lymph node positive, and 57% received some type of chemotherapy. At a median follow-up of 68 months, a significantly improved DFS was seen with exemestane plus OFS (91.1% v 87.3%; HR, 0.72; 95% CI, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 35 DECEMBER 1

Abstract CT013: NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC)

Background: T-DM1, an antibody-drug conjugate that delivers the maytansinoid antimicrotubule agent DM1 to antigen-expressing HER2+ cells thereby improving the therapeutic index, is FDA- approved as 2nd-line therapy in HER2+ MBC patients (pts) after prior trastuzumab (T) and a taxane. Most pts currently receive T and pertuzumab (P) as neoadjuvant for 1st-line therapy for MBC. A retrospective analysis of T-DM1 after T-P found a much lower tumor response rate (17%) than T-DM1 after T and taxane, as reported in EMILIA (43%). In NSABP FB-8, combining T, N, and paclitaxel achieved responses after T-DM1 progression, raising the possibility that N could reverse resistance to T-DM1. Methods: Eligible pts had prior T-P as neoadjuvant therapy for 1st-line metastatic treatment for HER2+ measurable disease, ECOG PS Results: The RP2D is still undergoing evaluation. 17 T-P resistant pts were enrolled. Treatment-related grade 3 toxicities included diarrhea (2 pts), thrombocytopenia (3 pts), hypertension (2 pts), ALT elevation (1 pt), nausea (1 pt), and neutropenia (1 pt). Of 14 pts who were evaluable after 2 cycles of therapy, 3 had CRs and 6 had PRs (ORR 64%). Conclusions: T-DM1 plus N was well tolerated at doses of 120, 160, and 200 mg/d. Anti-tumor activity did not appear to be dose-dependent. 5 evaluable pts treated at lowest dose of N (120 mg/d) responded. A randomized phase II study comparing N at 120 mg/d and 200 mg/d with T-DM1 is planned to better define efficacy and tolerance. Support: Puma Biotechnology Citation Format: Jame Abraham, Shannon L. Puhalla, Wiliam M. Sikov, Alberto J. Montero, Jan H. Beumer, Marc E. Buyse, Laura M. Adamson, Ashok Srinivasan, Katherine L. Pogue-Geile, Samuel A. Jacobs. NSABP FB-10: Phase Ib dose-escalation trial evaluating trastuzumab emtansine (T-DMI) with neratinib (N) in women with metastatic HER2+ breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT013. doi:10.1158/1538-7445.AM2017-CT013

Abstract P4-13-25: Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer

Background: Abemaciclib, a small molecule inhibitor of CDK4 and CDK6, induces G1 cell cycle arrest in Rb-proficient human cancers.1 The clinical safety profile of abemaciclib enables continuous oral dosing to achieve sustained target inhibition, resulting in single-agent antitumor activity against multiple human cancers. The drug also reaches relevant concentrations in the central nervous system and, in patients taking the drug orally, can be detected in the cerebrospinal fluid.2 For women with previously treated hormone receptor positive (HR+) metastatic breast cancer (MBC), abemaciclib as a single agent achieved a six-month clinical benefit rate of 61.1% and an objective response rate of 33.3%.3 Clinical trials investigating abemaciclib combined with fulvestrant4 or aromatase inhibitors5 have led to randomized Phase 3 studies for women with HR+ breast cancer.6,7 Methods: This Phase 1b study (NCT02057133) with multiple cohorts evaluates safety and tolerability of abemaciclib combined with endocrine or HER2-targeted therapies for MBC. Secondary objectives include pharmacokinetics (PK) and antitumor activity of abemaciclib when given in combination with other therapies. Cohorts were opened to enrollment sequentially. Patients with HR+ HER2 negative MBC received abemaciclib orally every 12 hours (Q12H) in combination with the following standard therapies daily until progression: letrozole (Part A), anastrozole (Part B), tamoxifen (Part C), exemestane (Part D), or exemestane plus everolimus (Part E). Patients with HER2 positive MBC received abemaciclib orally Q12H in combination with trastuzumab every 21 days until progression (Part F). Adverse events (AEs) were graded by NCI CTCAE v4.0 and tumor response was assessed radiographically using RECIST v1.1. Results: Abemaciclib has been combined with multiple targeted therapies for the treatment of women with MBC. We previously reported safety and early efficacy results for the combinations of abemaciclib with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus.5 Due to limited follow-up at that time, the efficacy results were not mature. Safety, PK, and efficacy results with approximately 6 months of additional follow-up will be reported across all parts of the study. The most common treatment-emergent AEs include effects on the gastrointestinal and hematopoietic systems. Consistent with previously reported results for both single-agent abemaciclib and the combination of abemaciclib with fulvestrant, tumor responses have been observed among women receiving abemaciclib in combination with targeted therapies for MBC. Conclusions: This study for women with MBC demonstrates the potential for abemaciclib to be combined with therapies targeting specific signaling pathways. References:1Gelbert et al. Invest New Drugs. 2014;32(5):825-37. 2Shapiro et al. J Clin Oncol 31, 2013 (suppl; abstr 2500). 3Tolaney et al. SABCS 2014: Abstract 763. 4Patnaik et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 534). 5Tolaney et al. J Clin Oncol 33, 2015 (suppl; abstr 522). 6Llombart et al. SABCS 2014: OT1-1-07 (MONARCH 2, NCT02107703). 7Goetz et al. J Clin Oncol 33, 2015 (suppl; abstr TPS624) (MONARCH 3, NCT02246621). Citation Format: Goetz MP, Beeram M, Beck T, Conlin AK, Dees EC, Dickler MN, Helsten TL, Conkling PR, Edenfield WJ, Richards DA, Turner PK, Cai N, Chan EM, Pant S, Becerra CH, Kalinsky K, Puhalla SL, Rexer BN, Burris HA, Tolaney SM. Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-25.

Sustained, Long-Term Maintenance of Remission with Single-Agent Veliparib in Recurrent Triple-Negative Breast Cancer

Triple-negative breast cancers (TNBC) have poorer outcomes than hormone positive or human epidermal growth factor receptor 2 (HER2)-positive breast cancers, with chemotherapy being the usual standard of care. Veliparib, a poly ADP-ribose polymerase (PARP) inhibitor, has been studied in both breast cancer susceptibility genes 1 and 2 (BRCA)-mutation related and sporadic cancers as a single agent and in combination with chemotherapy. Here, we describe a patient whose metastatic recurrence of TNBC was treated with combination chemotherapy and veliparib followed by maintenance single-therapy veliparib.

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer.

Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.