HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.
CCR Translation for This Article from HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab
1090 Background: Sunitinib (S) is an oral tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity. The primary objective of this trial was to assess the pathologic complete response rate (pCR) in patients (pts) treated with NC consisting of S with weekly paclitaxel (T) followed by doxorubicin and daily oral cyclophosphamide plus G-CSF (AC+G-CSF). Correlative studies including circulating biomarkers are reported separately. Methods: Pts with HER2 negative LABC or IBC were eligible for this multicenter, phase II trial. Pts received S 25 mg po daily with T 80 mg/m 2 IV Qweek (wk) x 12 wks, then AC+G-CSF (doxorubicin 24 mg/m 2 IV Qwk + oral cyclophosphamide 60 mg/m 2 po daily + G-CSF 5 mcg/kg SC days 2-7) x 15 wks. pCR in the breast and axilla was assessed at surgery, and the MDACC CPS+EG score (validated score combining clinical and pathologic results for predicting survival in the neoadjuvant setting) was calculated. Results: 70 pts (ages 33-79) were enrolled; 68 received protocol therapy. 37 (53%) had ER and/or PR positive tumors. 2 patients were unevaluable (hypersensitivity to T, toxicity possibly related to S) and 3 withdrew consent prior to surgery. 61 pts reported any grade AE in S+P period. Among grade 3 or 4 AEs, neutropenia was most common in S+P period occurring in 31/68 (46%). pCR in the breast was observed in 27% (17/63, 95% CI 17%-40%) and breast and axilla in 15/63 (24%). In pts with ER positive tumors, pCR rate in breast was 8/34 (24%) and 9/29 (31%) for pts with ER negative tumors. 18 evaluable pts (29%) had CPS+EG scores ≤2, 40 (63%) had CPS+EG scores of ≥3, and 5 had insufficient information to calculate the CPS+EG score. When response was defined as pCR and/or CPS+EG score ≤ 2, 28 pts (44%) were responders. Conclusions: NC with T+S followed by AC+G-CSF was well tolerated. Using a combined definition of response of pCR and/or CPS+EG score ≤2, 28/63 (44%) pts had response; 19/34 (56%) for ER positive and 9/29 (31%) for ER negative disease. The addition of S to NC may result in promising incremental benefit for pts with ER positive breast cancer. Clinical trial information: NCT00513695.
Abstract Introduction/Aims: DDIR signature, HRD, and stromal tumor infiltrating lymphocytes (sTIL) have each been associated with favorable outcomes in early stage TNBC. We assessed the overlap between these markers and created prognostic categories based on their combined use in a prospective trial of TNBC patients uniformly treated with adjuvant doxorubicin (A) and cyclophosphamide (C) on the SWOG S9313 trial. Methods: SWOG S9313 trial accrued 3,125 women with early stage breast cancer to two alternative dose schedules of AC, with no difference in outcomes between the two arms. 425 centrally determined TNBC cases from S9313 were identified. DDIR signature (score ≥ 0.3681 = DDIR+, Almac Diagnostic Services), HRD status (score ≥ 42 = HRD+, Myriad Genetics), and sTIL were assessed. Gene expression data (Xcel™ array) was subjected to claraT V3.0.0 biological signature analysis (Almac Diagnostic Services), and co-expression cluster analysis was used to identify signatures associated with DDIR and HRD status. The impact of dual classification by DDIR and HRD status (Group 1: DDIR+/HRD+, Group 2: DDIR+/HRD-, Group 3: DDIR-/HRD+, Group 4: DDIR-/HRD-) on disease free survival (DFS) and overall survival (OS) was examined using Cox regression with adjustment for randomized treatment assignment and nodal status. Results: For the 425 patients, median age was 45 years, 33% were node-positive, and 5-year DFS and OS were 74% and 82%, respectively. DDIR and HRD status was available for 89% each, sTIL% was available for 99%, and all three markers were available for 77% (328/425) of patients. 60% were DDIR+ and 65% HRD+. Among DDIR- tumors, 58% were HRD+. sTIL% was associated with DDIR status (P<0.0001) but not with HRD status (P=0.75). The proportion of patients in each group, median sTIL%, and 5-year DFS and OS for each group are outlined in Table 1. DFS and OS were similar for Groups 1, 2, and 3 but significantly lower for Group 4. As expected, cluster analysis showed that immune response signatures dominated Groups 1 and 2 regardless of HRD status. Group 3 tumors were characterized by over-representation of genomic instability signatures, a paucity of immune-related signatures, and low sTIL infiltration. Despite this immune-depleted phenotype, the 5-year OS for Group 3 was similar to that of the immune-enriched DDIR+ groups. Signatures associated with epithelial-mesenchymal transition, mast cell infiltration, and xenobiotic metabolism were over-represented in Group 4. Conclusions: Forty percent of patients with early stage TNBC demonstrate immune-deplete (DDIR-) phenotype, and within this phenotype, more than half demonstrate HRD+ status. HRD+ status within the immune-deplete phenotype predicts for better DFS and OS with adjuvant AC, probably due to underlying genomic instability and increased sensitivity to DNA damaging chemotherapy. Sixty percent of early stage TNBC patients demonstrate an immune-enriched (DDIR+) phenotype, and this phenotype is associated with improved survival with adjuvant AC chemotherapy regardless of HRD status. These findings provide important insights for patient selection and stratification in ongoing and future trials assessing DNA damaging therapy (e.g. PARPi, anthracyclines, platinum agents), immunotherapy, and their combinations in TNBC. Table 1Immune-Enriched GroupsImmune-Deplete GroupsGroup 1 DDIR+/HRD+ N=137 (42%)Group 2 DDIR+/HRD- N=59 (18%)Group 3 DDIR-/HRD+ N=77 (23%)Group 4 DDIR-/HRD- N=55 (17%)5-year DFS82%74%74%56%P=0.001 (Group 1 vs 4); P=0.006 (Group 2 vs 4); P=0.016 (Group 3 vs 4); P=NS (Groups 1 vs 2, 1 vs 3, and 2 vs 3)5-year OS88%86%83%69%P=0.001 (Group 1 vs 4); P=0.003 (Group 2 vs 4); P=0.026 (Group 3 vs 4); P=NS (Group 1 vs 2, 1 vs 3, and 2 vs 3)Median sTIL (%)20%20%5%5%P<0.0001 (Group 1 vs 3); P<0.0001 (Group 2 vs 3); P=NS (Group 1 vs 2, 3 vs 4) Citation Format: Shane R Stecklein, William Barlow, Lajos Pusztai, Kirsten Timms, Richard Kennedy, Sunil Badve, Yesim Gökmen-Polar, Peggy Porter, Hannah Linden, Debu Tripathy, Gabriel N Hortobagyi, Andrew K Godwin, Alastair Thompson, Daniel Hayes, Priyanka Sharma. Classification of triple negative breast cancer (TNBC) by DNA damage immune response (DDIR) signature and homologous recombination deficiency (HRD) status: Analysis of SWOG S9313 adjuvant trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-05.
2569 Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) have activity in tumors with DNA repair defects, including BRCA 1/2 deficient cancers. CP is synergistic with the PARPi veliparib in xenografts, and has anti-tumor activity in TNBC and BRCA1 deficient breast cancer. VNR shows preclinical synergy with CP and the combination has efficacy in metastatic breast cancer (MBC). We hypothesize that veliparib combined with CP and VNR is active in TNBC and will be most effective in tumors with DNA repair defects. Methods: To determine maximum tolerated dose (MTD), pharmacokinetic (PK) and pharmacodynamic profiles, and anti-tumor activity, patients (pts) with TNBC and/or BRCA1/2+ MBC received CP 75 mg/m2 day 1, VNR 25 mg/m2days 1, 8 and escalating doses of veliparib (V) orally BID days 1-14, every 21 days for 6-10 cycles followed by maintenance V. Results: 45 pts enrolled in 9 cohorts. Treatment was tolerated well; MTD was not reached. 36 pts (80%) had at least 1 prior metastatic regimen (range 1-11). BRCA mutation status was: BRCA1+ (n=9); BRCA2+ (n=3); negative (n=24); unknown (n=9). BID V dose cohorts were: 20 mg (n=4); 30 mg (n=3); 40 mg (n=6); 60 mg (n=8); 80 mg (n=5 ); 120 mg (n=6); 160 mg (n=3); 200 mg (n=7); and 300 mg (n=3). DLT occurred at 40 mg BID in 1 pt with grade (gr) 4 thrombocytopenia, 60 mg BID (gr 4 neutropenia + fever, n=1), and 200 mg BID (gr 3 neutropenia + fever, n=1). Most common adverse events (AEs) were nausea, anemia, fatigue, mainly gr 1/2. Most common gr 3/4 AEs were neutropenia (n=13), anemia (n=11), thrombocytopenia (n=6). Of 38 evaluable pts, 21 (55%) responded (2 CR, 19 PR), 13 (34%) had SD, and 4 had PD, as best response. One pt with CR remains on trial for 42+ cycles. Response was 73% in BRCA 1/2+ pts (6/11 PR; 2/11 CR), 53% in BRCA1/2- pts (11/21 PR) and 33% in unknown status pts (2/6 PR). Analyses of PK and correlative predictors of response will be presented. Conclusions: Veliparib at the recommended phase II dose of 300mg BID combined with CP and VNR is well tolerated. BRCA mutation carriers and pts with sporadic TNBC, including heavily pretreated pts, responded. We plan to investigate the contribution of veliparib to cisplatin-based therapy in a randomized trial. Clinical trial information: NCT01104259.
575 Background: Response to neoadjuvant therapy in the primary tumor and nodal metastasis predicts benefit to patients as shown in several large clinical trials. We have previously shown that changes in tumor blood flow (BF) measured by [15O]-water PET predict pathologic primary tumor response. We now test whether primary tumor blood flow changes also predict axillary nodal metastases response and post-therapy lymph node status among women with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy. Methds: Fifty-five women with a primary diagnosis of LABC underwent dynamic [15O]-water PET scans prior to and at midpoint of neoadjuvant chemotherapy. We evaluated associations between tumor BF changes and pathologic primary tumor response: categorized as complete (CR), partial (PR) or no response (NR). We also assessed the relationship between primary tumor BF changes and post-therapy axillary lymph node status, categorizing the high risk (HR) group as 4+ nodes with extracapsular extension (ECE, n=12) versus the lower risk (LR) group with either fewer than 4+ nodes or without ECE (n=43). Results: The median changes in BF versus tumor response were: CR = -77%, PR = -40%, and, NR = +20% (P = <0.001). For axillary node response, the median BF change among HR patients was +20% versus - 49% among LR patients (P = 0.004). Eight of 17 patients with an increase in tumor blood flow were HR whereas 4/38 patients with decreased tumor blood flow were HR (P = 0.002). Conclusions: Change in primary tumor blood flow over the course of neoadjuvant chemotherapy predicts pathologic response to treatment with a substantial decrease observed among CRs. An increase in primary tumor BF with treatment portends significant residual primary tumor and a nearly 50% chance of very high-risk nodal disease post-therapy. No significant financial relationships to disclose.
Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases. Uncommon BC presentations like male, inflammatory and pregnancy-related BC pose challenges. Emerging therapeutic strategies targeting genetic alterations or immune microenvironment are being explored.
