bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P6-13-04: Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials
Authors: Ragaz J , Qian H , Wong H , Wilson KS , Shakeraneh S , Spinelli JJ
Published: May 2019

OBJECTIVE: To quantitate breast cancer incidence (BrCa-I) and mortality (BrCa-M) outcome differences between the two Women's Health Initiative (WHI) HRT trials,1,2 the ratio of hazards was calculated for estrogen-alone based hormone replacement therapy (E-HRT) vs. placebo (P), and E + progestin Provera (ProgProv) combination HRT vs. P trials.

METHODS: Hazard ratios (HR) of BrCa-I and BrCa-M and 95% confidence intervals (CI) were obtained from both WHI HRT trials. Subsequently, to compare BrCa outcomes between E-HRT vs. E + ProgProv, the ratios of HRs between the trials (HR1/HR2) were estimated separately for i. BrCa-I all women, ii. BrCa-I low Gail score (Gail score <1.75*), and iii. BrCa-M. The 95% CI was derived through logarithmic transformation of the 95% CI originally reported.

RESULTS:

Outcome Comparison, the two WHI HRT randomized trials. Ratio of Hazards, BrCa Incidence and BrCa mortality E-HRT vs. P, HR1 (95% CI)E-HRT + ProgProv vs. P, HR2 (95% CI)HR1/HR2 (95% CI)pBrCa-I All Woman10.77 (0.62-0.95)1.25 (1.07-1.46)0.62 (0.47-0.80)0.0004BrCa-I Low Gail Score* (Gail score <1.75)10.65 (0.50-0.86)1.24 (1.01-1.51)0.53 (0.38-0.74)0.0002BrCa-M20.55 (0.33-0.92)1.44 (0.97-2.15)0.38 (0.20-0.75)0.004*Gail score <1.75; HRs calculated from Reference 1, Figure 3

CONCLUSIONS: Our calculations show that the different outcomes between the two WHI HRT trials, estimated as ratio of hazards, are highly significant on statistical basis, both for BrCa incidence and for BrCa mortality. These findings highlight the potential carcinogenic impact of ProgProv and the major public health benefits of HRT based on E alone.

REFERENCES:

1. Anderson GL, Chlebowski RT, Aragaki AK, et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. The Lancet Oncology 2012;13:476-86.

2. Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials. JAMA 2017;318:927-38.

Citation Format: Ragaz J, Qian H, Wong H, Wilson KS, Shakeraneh S, Spinelli JJ. Estrogen-alone based hormone replacement therapy (HRT) reduces breast cancer (BrCa) incidence and mortality whereas estrogen plus progestin Provera based HRT increases both BrCa incidence and BrCa mortality: A comparative analysis of Women's Health Initiative trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-13-04.
Abstract P6-14-05: Withdrawn
Authors: Esser MR , Rowe JJ , McCann ML , Nicholas-Alexander M , Helck EP , Lewis SM
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Esser MR, Rowe JJ, McCann ML, Nicholas-Alexander M, Helck EP, Lewis SM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-14-05.
Abstract P6-17-01: Withdrawn
Authors: Tolaney SM , Wardley AM , Zambelli S , Hilton JF , Troso-Sandoval TA , Ricci F , Im S-A , Kim S-B , Johnston SR , Chan A , Goel S , Catron K , Yang Z , Gainford C , André F
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Tolaney SM, Wardley AM, Zambelli S, Hilton JF, Troso-Sandoval TA, Ricci F, Im S-A, Kim S-B, Johnston SR, Chan A, Goel S, Catron K, Yang Z, Gainford C, André F. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-01.
Abstract P6-17-16: Efficacy and safety of shorter duration of adjuvant trastuzumab for patients with HER2 positive early breast cancer: A meta-analysis of randomized controlled trials
Authors: Li J , Wang G , Wu Q , Chen C , Tu Y , Yao F , Wei W , Sun S , Santa-Maria CA , Geng P
Published: May 2019

Background: Trastuzumab has been shown to be able to improve disease free survival(DFS) and overall survival(OS) in HER2-positive breast cancer patients. Adjuvant trastuzumab is empirically recommended for 1 year as a standard regimen. However, several studies claimed that shorter duration of adjuvant trastuzumab is non-inferior to 12 months treatment with reduced cardiac toxicities and costs.

Methods: PubMed, EMBASE, Cochrane Library, Google scholar Web, ISI Web of Science, BIOSIS and CNKI, and major conference abstracts were searched systematically in June 2018 to identify eligible non-inferiority studies comparing the intervention outcomes of adjuvant trastuzumab in chemotherapy for women with HER-2 positive breast cancer between short-term and 1-year treatments. Hazard-Ratios(HR) and corresponding 95% Confidence Intervals(CI) were calculated to compare OS and DFS of trastuzumab between short-term and long-term treatments. Pooled data of Odds-Ratio was analyzed for cardiac toxicities.

Results: 5 articles were finally eligible in the study. Totally, there were 11,376 women with HER-2 positive early breast cancer, with 5,684 in short-term group and 5,692 in the 1-year group. We found a distinct difference of DFS (HR=1.19, 95% CI=1.08-1.30) and OS (HR=1.22, 95% CI=1.07-1.39) between short-term and 12 months trastuzumab in the total analysis, which demonstrated short-term treatment exhibited a worsening trend on DFS and OS. Subgroup analysis was performed based on estrogen receptor (ER) and lymph node status, and no statistical interaction could be found(p=0.12, 0.52, respectively). The two groups with different duration of trastuzumab treatment displayed statistically significant difference for cardiotoxicities, which favored shorter duration(OR=0.54, 95% CI=0.38-0.77).

Conclusions: 1-year adjuvant trastuzumab remains the standard strategy for HER2 positive early breast cancer, however, a concomitant higher risk of associated cardiac adverse effects should not be ignored.

Citation Format: Li J, Wang G, Wu Q, Chen C, Tu Y, Yao F, Wei W, Sun S, Santa-Maria CA, Geng P. Efficacy and safety of shorter duration of adjuvant trastuzumab for patients with HER2 positive early breast cancer: A meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-16.
Abstract P6-17-20: Withdrawn
Authors: Junttila TT , Ellerman D , Lombana N , Hristopoulos M , Clark R , Li J , Vij R , Koerber JT , Johnston J , Shelton A , Mai E , Gadkar K , Lo AA , Totpal K , Prell R , Lee G , Spiess C , Slaga D
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Junttila TT, Ellerman D, Lombana N, Hristopoulos M, Clark R, Li J, Vij R, Koerber JT, Johnston J, Shelton A, Mai E, Gadkar K, Lo AA, Totpal K, Prell R, Lee G, Spiess C, Slaga D. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-20.
Abstract P6-17-29: Withdrawn
Authors: Veitch ZW , Bedard P , Tang PA , Conway JL , Ribnikar D , Albaba H , King K , Lupichuk S , Cescon D
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Veitch ZW, Bedard P, Tang PA, Conway JL, Ribnikar D, Albaba H, King K, Lupichuk S, Cescon D. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-29.
Abstract P6-17-30: Changes in patient, tumor, and treatment characteristics over time in first-line trastuzumab plus taxane (paclitaxel/docetaxel) arms in HER2-positive metastatic breast cancer trials
Authors: Badovinac Crnjevic T , Restuccia E , Michielin F , Eng-Wong J , Nüesch E
Published: May 2019

Background:

A retrospective analysis showed improved progression-free survival and consistent underestimation of trastuzumab (H) + taxane (T) efficacy assumptions in first-line (1L) human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) trials over time (ISCB 2016). We evaluated changes in baseline and treatment characteristics and the safety profile of H+T in 1L HER2-positive MBC trials conducted during 1995–2015.

Methods:

Trial-level data on patient, tumor, and treatment characteristics and safety profiles in H+T arms of 15 randomized trials were extracted from published data and clinical study reports. Characteristic and safety profile changes over time were explored by weighted regression; relevance was assessed by F-test.

Results:

Patient and tumor characteristics were generally stable over time. We observed relevant changes in types of adjuvant therapy used. Serious adverse events (SAEs) and study withdrawals due to Aes decreased over time; rates of treatment discontinuation due to Aes increased.

 No. of trials (patients)Difference in patients with characteristic per 5 years, % (95% CI)P valueBaseline characteristics   Median age15 (2895)0.5 (0.1, 0.9)*.28ECOG status 012 (2472)0.2 (-1.1, 1.6).87Hormone receptor-positive11 (2124)1.3 (-1.1, 3.6).61HER2 IHC 3+8 (1657)5.8 (3.0, 8.6).08Visceral disease10 (1970)0.5 (-2.5, 3.6).86Adjuvant therapy   Hormonal therapy11 (2194)-10.1 (-12.4, -7.8).002Radiotherapy9 (2010)-4.2 -5.8, -2.6).035HER2-targeted therapy9 (2176)20.2 (13.0, 27.4).026Chemotherapy15 (2893)-7.0 (-9.2, -4.7).008Safety   Grade 3+ AE6 (1342)-15.4 (-28.4, -2.5).30SAE7 (1462)-12.6 (-15.4, -9.8).006Study withdrawal due to AE8 (1525)-6.8 (-9.0, -4.5).023Treatment discontinuation due to AE6 (1370)11.5 (6.7, 16.3).075*Years (95% CI). AE, adverse events; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IHC, immunohistochemistry; SAE, serious adverse events.

Conclusions:

In 1L HER2-positive MBC trials, the percentage of patients who received adjuvant chemo-, hormonal, and radio-therapy decreased from 1995 to 2015. These changes in treatment patterns suggest a shift towards a higher percentage of patients with de novo metastatic vs recurrent disease in 1L MBC trials over time. Adjuvant H use increased following approval in 2005 as expected. While SAEs decreased over time, no firm conclusions on safety management can be made.

Citation Format: Badovinac Crnjevic T, Restuccia E, Michielin F, Eng-Wong J, Nüesch E. Changes in patient, tumor, and treatment characteristics over time in first-line trastuzumab plus taxane (paclitaxel/docetaxel) arms in HER2-positive metastatic breast cancer trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-30.
Abstract P6-17-32: Impact of the line of treatment on progression-free survival in patients treated with T-DM1 for metastatic breast cancer
Authors: Duhoux FP , Dufour V , van Maanen A , Berliere M , Taylor D , Canon J-L
Published: May 2019

Background Trastuzumab emtansine (T-DM1) is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) receptors, conjugated with a cytotoxic component (a microtubule inhibitor). It is indicated as second-line treatment for HER2-positive metastatic or unresectable locally advanced breast cancer, after progression on trastuzumab and a taxane-based chemotherapy.

In HER2-negative metastatic breast cancer, progression-free survival (PFS) declines with each line of therapy, while patients with HER2-positive disease receive the most lines of chemotherapy and the longest duration for every line. We wished to investigate whether the line of treatment in which T-DM1 is administered has an impact on PFS. We also wished to explore whether prior treatment with capecitabine / lapatinib or pertuzumab had an impact on PFS, as none of the patients included in the registration trial had received these treatments before their inclusion in the trial.

Methods This is a multicenter retrospective study performed in 3 Belgian institutions. All patients received T-DM1 for HER2 positive metastatic or unresectable locally advanced breast cancer. The primary outcome was PFS with T-DM1, defined as the period between the first administration of T-DM1 and the first radiological or clinical assessment demonstrating progression of the disease.

Results We included 51 patients. One patient had to be excluded from the analyses because she no longer had HER positive disease. The median PFS was 9.01 months. The line of treatment in which T-DM1 was administered had no influence on PFS (hazard ratio 0.976, CI95 0.835-1.142).

There was no statistically significant difference in PFS between patients who had not received capecitabine / lapatinib before T-DM1 and those who had (9.11 vs 8.91 months, p-value 0.466).

Median PFS was 10.07 months when T-DM1 was administered prior to pertuzumab, and 5 months when administered after pertuzumab. Patients who received pertuzumab before T-DM1 thus tended to exhibit a shorter PFS. However, this difference is not statistically significant (p-value 0.096).

Conclusions Unlike with conventional chemotherapy, the line of treatment in which T-DM1 is administered does not influence PFS in metastatic breast cancer patients.

Citation Format: Duhoux FP, Dufour V, van Maanen A, Berliere M, Taylor D, Canon J-L. Impact of the line of treatment on progression-free survival in patients treated with T-DM1 for metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-32.
Abstract P6-17-37: Therapy landscape of patients with metastatic, HER2 positive breast cancer - Data from the real world breast cancer registry PRAEGNANT (NCT02338167)
Authors: Lux MP , Hartkopf AD , Huober J , Volz B , Taran F-A , Overkamp F , Hadji P , Tesch H , Haeberle L , Ettl J , Lueftner DI , Wallwiener M , Müller V , Beckmann MW , Belleville E , Wimberger P , Hielscher C , Geberth M , Lermann J , Abenhardt W , Kurbacher C , Wuerstlein R , Thomssen C , Untch M , Fasching PA , Janni W , Fehm TN , Wallwiener D , Brucker SY , Schneeweiss A , Kolberg H-C
Published: May 2019

Purpose:

This analysis describes comprehensive real-world data concerning the use of anti-HER2 therapies in HER2 positive metastatic breast cancer (MBC). Specifically, it describes the therapy patterns of treatments with trastuzumab (TZM), pertuzumab+trastuzumab (PTZ/TZM), lapatinib (LAP) and trastuzumab emtansine (T-DM1).

Methods:

The PRAEGNANT study is a real-time, real-world registry for patients with MBC. Patients can be registered for PRAEGNANT at any time during the course of their metastatic disease and are followed up until death. All therapy lines are documented. This analysis presents the utilization of anti-HER2 therapies as well as therapy sequences.

Results:

Of 1936 patients within PRAEGNANT at the time of database closure 451 were HER2 positive (23.3%). Within the analysis set (417 patients after an unilateral breast cancer diagnosis), of which 53% were included in PRAEGNANT in the 1stline setting, 241 were treated with TZM (58%), 237 with PTZ (57%), 85 with LAP (20%) and 125 with T-DM1 (30%) during the course of their therapies. The sequence PTZ/TZMàT-DM1 was given to 51 patients (12%). Worse ECOG, negative hormone receptor status, and visceral or brain metastases were associated with a more frequent use of this therapy sequence. Most patients received T-DM1 after a therapy with pertuzumab.

Conclusions:

Both novel therapies (PTZ/TZM and T-DM1) are utilized in a high proportion of HER2 positive breast cancer patients. As most patients receive T-DM1 after pertuzumab real world data might help to understand whether this sequence has similar efficacy like in the approval study.

Citation Format: Lux MP, Hartkopf AD, Huober J, Volz B, Taran F-A, Overkamp F, Hadji P, Tesch H, Haeberle L, Ettl J, Lueftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Fasching PA, Janni W, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A, Kolberg H-C. Therapy landscape of patients with metastatic, HER2 positive breast cancer - Data from the real world breast cancer registry PRAEGNANT (NCT02338167) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-37.
Abstract P6-17-39: BAT8001, a potent anti-HER2 antibody-drug conjugate with a novel stable linker for the treatment of HER2-positive breast cancer
Authors: Tang W , Deng X , Ou Z , Gan J , Dong Q , Tan B , Lu L , Chen B , Bao C , Li S , Thomas B , Yu J-C
Published: May 2019

Overexpression of HER2 occurs in approximately 20% of breast cancers and is associated with shortened survival. Trastuzumab emtansine (T-DM1), an anti-HER2 ADC, has shown efficacy in HER2-positive breast cancer patients and was approved by the FDA and EMA for advanced HER2-positive breast cancer. However T-DM1 causes grade 3 and 4 thrombocytopenia in up to 14.5% of patients as its major toxicity. The thrombocytopenia is likely caused by one of T-DM1's catabolites and payload, DM1, indicating T-DM1's linker can be cleaved. Here we adopted a novel noncleavable linker and created an anti-HER2 ADC, BAT8001, which is expected be efficacious in HER2-positive breast cancer and have a better side effect profile relative to T-DM1 due to the stability of BAT8001's noncleavable linker. BAT8001 is internalized in HER2-positive cancer cells. It inhibits proliferation of HER2-positive tumor cells with IC50s of ˜0.1 nM, similar to the potency of T-DM1. BAT8001 also induces apoptosis in HER2-positive cancer cells. In both cell-line and patient-derived mouse xenograft (PDX) models, BAT8001 demonstrates strong inhibition activity on tumor growth. For example, in a cell-line model of breast cancer (BT474), BAT8001 demonstrates potent activity with complete responses in all animals tested at the 15mg/kg dose level. Pharmacokinetics studies in monkey reveals BAT8001 has similar Cmax, AUC, and t1/2 as T-DM1. The major catabolite of BAT8001 is the Cys-linker-payload containing product. No free payload is observed. This compares favorably with T-DM1 where free DM1, T-DM1's payload, is one of the major catabolites. In a multiple dose toxicity study, BAT8001 had a NOAEL of 15 mg/kg versus 10 mg/kg for T-DM1. BAT8001 exhibits similar potency to T-DM1 on inhibiting HER2-positive cell proliferation and tumor growth, yet demonstrates better multiple dose toxicity than T-DM1. The improved toxicity profile of BAT8001 suggests that the novel noncleavable linker utilized in BAT8001 is more stable than the linker utilized in T-DM1. BAT8001 is very efficacious in cell-line xenograft models of breast cancer. The preclinical profile of BAT8001 warrants further development for the treatment of breast cancer and other HER2-positive cancers.

Citation Format: Tang W, Deng X, Ou Z, Gan J, Dong Q, Tan B, Lu L, Chen B, Bao C, Li S, Thomas B, Yu J-C. BAT8001, a potent anti-HER2 antibody-drug conjugate with a novel stable linker for the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-39.
Abstract P6-18-01: Treatment benefit of ribociclib + letrozole in patients with de novo disease and visceral metastases from the MONALEESA-2 study
Authors: O'Shaughnessy JA , Arteaga CL , Hart LL , Lindquist DL , Beck JT , Purkayastha DD , Caria N , Hortobagyi GN
Published: May 2019

Background: Ribociclib (ribo) + letrozole (LET) demonstrated efficacy and safety in first-line treatment of patients (pts) with hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC). Most endocrine therapy (ET)–naive pts with de novo ABC respond to ET, but first-line monotherapy with ET or fulvestrant elicited only moderate efficacy in the FALCON study of pts with visceral metastases (mets). Visceral mets are associated with poor prognosis and may warrant novel treatment options in addition to ET. Here, we present clinical outcomes of treatment with ribo in pts with de novo ABC and visceral mets.

Methods: In the MONALEESA-2 study, postmenopausal women with HR+, HER2− ABC (N=668) were randomized (1:1) to receive either ribo 600 mg/d or placebo (3 wk on/1 wk off) + LET 2.5 mg/d (continuous). The primary endpoint was median progression-free survival (mPFS).

Results: All pts in this analysis (n=227) had de novo ABC; 108 pts had visceral mets (ribo, n=53; placebo, n=55). Baseline characteristics were similar between the ribo and placebo groups. The median follow-up time was 26.4 months. In pts with visceral mets, mPFS was significantly higher in the ribo group (30.3 months) than in the placebo group (14.1 months; hazard ratio, 0.52; 95% CI, 0.295–0.905; P=0.019). Rates of PFS in these pts in the ribo vs placebo group, respectively, were 76% vs 60% at 12 months and 60% vs 36% at 24 months. Among the pts with visceral mets, clinical benefit rate (CBR) was 79% vs 71% in the ribo vs placebo group, and overall response rate (ORR) in pts with measurable disease at baseline was 55% vs 46%, respectively. In pts without visceral mets (ribo, n=61; placebo, n=58), PFS rates in the ribo vs placebo group, respectively, were 87% vs 72% at 12 months and 66% vs 51% at 24 months. Safety results were consistent with the overall population, and responses were durable with ribo + LET irrespective of whether the pts had visceral or nonvisceral mets.

Conclusions: Clinical outcomes from this analysis of the MONALEESA-2 study are consistent with those of the overall population, and ribo + LET prolonged the mPFS and improved ORR and CBR in pts with de novo ABC with visceral mets vs placebo + LET.

Citation Format: O'Shaughnessy JA, Arteaga CL, Hart LL, Lindquist DL, Beck JT, Purkayastha DD, Caria N, Hortobagyi GN. Treatment benefit of ribociclib + letrozole in patients with de novo disease and visceral metastases from the MONALEESA-2 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-01.
Abstract P6-18-13: Identification of optimal combination therapy partners for PI3K/Akt/mTOR pathway inhibitor in triple negative breast cancer
Authors: Shariati M , Paez-Arango N , Bristow CA , Evans KW , Peoples MD , Carugo A , Heffernan TP , Meric-Bernstam F
Published: May 2019

Triple-negative breast cancer (TNBC) is among the most aggressive subtypes, accounts for 10-15% of all breast cancer cases and is characterized by a lack of hormone receptors with a low overall survival rate. Due to the heterogeneity nature of this disease, the absence of validated molecular targets makes it unresponsive to conventional therapies. PI3K/Akt/mTOR pathway is aberrantly activated in TNBC, but single agent therapy is commonly subject to resistance. The goal of this study is to identify the genes that can be targeted to enhance the efficacy of mTOR inhibitor TAK228, an agent that is being investigated as a treatment for advanced solid tumors, in TNBC with PI3K pathway activation. We utilized an in vivo pooled barcoded shRNA library screening to determine the genes that have the potential to be used as TAK228 synthetic lethal partners. Using deep sequencing analysis of the shRNA profiles, we identified several genes whose loss of function conferred synthetic lethality in the presence of TAK228. We found that targeting the candidate genes (WEE1, BMX and MAPK15) with their inhibitors (AZD1775, Ibrutinib and Sunitinib) did not significantly affect the viability, however combination treatment of these agents with TAK228 induced a robust growth inhibition and demonstrated a significant synergy in MDA-MB-468 cell lines. Investigating the activation of relevant survival signaling pathways will further elucidate the mechanism of synthetic lethal interaction. These observations provide a promising rational strategy for the treatment of TNBC with PI3K pathway aberration.

Citation Format: Shariati M, Paez-Arango N, Bristow CA, Evans KW, Peoples MD, Carugo A, Heffernan TP, Meric-Bernstam F. Identification of optimal combination therapy partners for PI3K/Akt/mTOR pathway inhibitor in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-13.
Abstract P6-18-33: GI toxicities in metastatic breast cancer: A comprehensive literature review
Authors: Disher T , Siddiqui M , Mitra D , Cameron C , Zhan L , Iyer S
Published: May 2019

Background

Treatments for advanced or metastatic breast cancer (aBC/mBC) are associated with gastrointestinal (GI) toxicities. The objective of this study was to assess the association between GI toxicities in mBC/aBC and health-related quality of life (HRQoL) and economic burden.

Methods

We conducted a comprehensive literature search of the Cochrane Central Register of Controlled Trials (2017), NHS Economic Evaluation Database (2016), Embase (1988 – 2017 week 34), and Ovid MEDLINE (1946 to August 2017). Eligible studies evaluated an intervention/comparator treatment in adult patients (age ≥18 years) with aBC/mBC and reported a direct connection between GI toxicities (ie, diarrhea, constipation, nausea, vomiting) and HRQoL and economic evidence. All studies published from January 2000 to August 2017 were assessed for eligibility. Editorials, case reports, conference abstracts, and studies of early, locally advanced, or inflammatory BC were excluded. Abstract and title screening, and full-text screening were conducted by single reviewers. Data were extracted by a single reviewer and verified by a second. Results were synthesized narratively.

Results

Database searches identified 3,428 articles; an additional 16 articles were identified through other sources. Ninety-four studies underwent full-text review, of which 27 reported a direct connection between GI toxicities and HRQoL (n = 11) and economic burden (n = 19). Some studies reported both HRQoL and economic data.

Patients identified treatment-related adverse events (AEs), such as GI events, as an important aspect of treatment that can affect therapy choice, discontinuation, and switching. Generally, patients with mBC had lower HRQoL than other BC groups, and increasing toxicity was associated with a greater degree of HRQoL impairment. When patients were asked to rank which AEs they most wanted to avoid, only pain ranked higher than nausea and vomiting. In a willingness to pay study, women with mBC were willing to pay $3,894 (2014 USD) per year to avoid severe diarrhea and $3,211 to avoid severe nausea.

Gastrointestinal events were among the costliest class of AEs, with mean costs as high as $4,809 (2016 USD) per episode; costs increased by 24% if events were persistent or recurrent.

Conclusions

Gastrointestinal toxicities are common in patients with aBC/mBC and have significant consequences for HRQoL and system-level economic outcomes. Frequency and implications of GI effects of treatment regimens should be considered carefully during patient counseling,, prescribing and coverage decisions in metastatic breast cancer.

Citation Format: Disher T, Siddiqui M, Mitra D, Cameron C, Zhan L, Iyer S. GI toxicities in metastatic breast cancer: A comprehensive literature review [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-33.
Abstract P6-19-06: Breast conservation surgery in male breast cancer: A systematic literature review
Authors: Fisher CS , de la Cruz L , Joshi S , Mah T-J , Blankenship S , Thiruchelvam P
Published: May 2019

BACKGROUND

Male breast cancer (BC) incidence is low and management is extrapolated from female BC. Breast conservation surgery (BCS) is commonly used for female BC, however, mastectomy remains the most frequently used surgical procedure for male breast cancer. We performed a literature review to assess the use of BCS in male BC as well as outcomes following BCS.

METHODS

A systematic literature review identified peer-reviewed articles in PubMed evaluating male BC and surgery. Abstracts were screened to identify studies that measured overall survival (OS), disease-free survival (DFS), or local recurrence (LR) in patients undergoing BCS. For all studies, we extracted the total number of patients and number of BCS cases. Of patients undergoing BCS, we further extracted mean age, mean follow-up time, clinical stage, type of axillary surgery [sentinel lymph node biopsy (SLNB), axillary lymph node dissection (ALND)], radiation therapy, hormonal therapy, and chemotherapy. Weighted averages, based on number of patients in each study, were performed for LR, DFS and 5-year OS. The time period for LR and DFS was the duration of follow-up time for each study.

RESULTS

The literature search yielded 4341 articles. Twelve studies published from 1998 to 2016 met the inclusion criteria and were selected for the systematic literature review. Among the 12,616 male breast surgery cases included, 1,633 (12.9%) underwent BCS. Only patients who underwent BCS were included in our analysis. The mean follow-up time was 54.4 months and mean age was 62.4 with stage II as the most common presentation. Two studies reported that 50-71.4% of patients underwent SLNB and 4 studies reported ALND in 14.3-100%. Seven studies reported that adjuvant radiation therapy was administered in 12.0-100% of 474 total patients undergoing BCS. Four studies reported use of hormonal therapy in 73.8-100% of patients. Four studies reported use of chemotherapy in 25-66.7% of patients. Seven studies reported LR among 122 patients, with a weighted average 11.8%. Four studies reported on 5-year OS in 1511 patients, with a weighted average of 85.8%.

CONCLUSION

While less commonly used than mastectomy, BCS can be considered a safe alternative in the surgical treatment of male BC. We have demonstrated that the use of adjuvant radiation following BCS is variable in this patient group. Future research should focus on better standardization of local therapy for male BC and improved reporting of outcomes.

Citation Format: Fisher CS, de la Cruz L, Joshi S, Mah T-J, Blankenship S, Thiruchelvam P. Breast conservation surgery in male breast cancer: A systematic literature review [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-19-06.
Abstract P6-20-05: Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation
Authors: Na B , Yu X , Wither T , Gilleran J , Yao M , Foo TK , Chen C , Moore D , Xia B , Lin Y , Kimball D , Ganesan S , Carpizo D
Published: May 2019

Triple negative breast cancer (TNBC) is an aggressive subset for which novel therapeutic approaches are needed. A significant proportion of TNBC patients harbor either germline or somatic mutations in BRCA1, or epigenetic silencing of BRCA1, which renders them deficient in DNA repair. Virtually all BRCA1 deficient breast cancers harbor mutations in TP53 suggesting that inactivation of p53 is a requirement for tumor progression in the setting of BRCA1 deficiency. Due to this dependency, we hypothesized that restoring wild type p53 function in BRCA1 deficient breast cancer would be therapeutic. The majority of TP53 mutations are missense, which generate a defective protein that potentially can be targeted with small molecules. Zinc Metallochaperones (ZMCs) are a new class of anti-cancer drugs that reactivate a class of zinc deficient mutant TP53 alleles by restoring zinc binding. Using ZMC1 in human breast cancer cell lines expressing the zinc deficient p53R175H, we demonstrate that loss of BRCA1 sensitizes cells to mutant p53 reactivation. Using genetically engineered murine mammary tumor models with Brca1 deficiency, we demonstrate that ZMC1 significantly improves survival in mice bearing tumors harboring the zinc deficient Trp53R172H allele but not the Trp53 null allele. We synthesized a novel formulation of ZMC1 (Zn-1), in which the drug is made in complex with zinc to improve zinc delivery, and demonstrate that Zn-1 has increased efficacy over ZMC1. Furthermore, we show that ZMC1 plus olaparib is a highly effective combination for tumors expressing the p53R172H mutant. In conclusion, we have validated preclinically a novel therapeutic approach for BRCA1 deficient breast cancer through reactivation of mutant p53.

Citation Format: Na B, Yu X, Wither T, Gilleran J, Yao M, Foo TK, Chen C, Moore D, Xia B, Lin Y, Kimball D, Ganesan S, Carpizo D. Therapeutic targeting of BRCA1 and TP53 mutant breast cancer through mutant p53 reactivation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-05.
Abstract P6-20-15: Characterization of a novel prognostic and targetable modulator of the Wnt/β-catenin signaling pathway in breast cancers
Authors: Bunnag N , Yuan Y , Cai W , Suresh J , Young Bok L , Deog Joong K , Tolwinski N , Kumar AP
Published: May 2019

Mortality in metastatic triple negative breast cancer (TNBC) remains high due to a lack of targeted therapy options. Consequently, there is a pressing need to identify prognostic markers and therapeutic targets for TNBC. Our group identified the DEAD-box RNA helicase DP103 as a novel prognostic biomarker and metastasis-driving oncogene enriched in TNBC. Aberrant Wnt/β-catenin signaling has been implicated for driving growth and metastasis of many cancers, like TNBC. Our studies found that the depletion of DP103 in metastatic TNBC cells resulted in decreased Wnt activity and expression of downstream Wnt target genes such as Axin2 and c-Myc. In addition, stimulation of the Wnt pathway via GSK3β inhibition or Wnt-3a recombinant protein significantly increased the transcriptional expression of DP103, indicating a possible positive feedback loop. To validate this new role for DP103 in regulating the Wnt/β-catenin signaling pathway in vivo, we developed a novel Drosophila stem cell and tumor model by generating a genetic mosaic of oncogenic Ras and β-catenin in Drosophila. The co-expression of these oncogenes caused benign tumor formation in Drosophila larval tissue that were visualized and used to identify key genetic modifiers necessary for growth and invasion into neighboring tissues. RX-5902, a novel Wnt/β-catenin modulator preventing the nuclear translocation of β-catenin via phosphorylated p68 decreased the transcriptional expression of DP103 and inhibited tumor formation as observed in our Drosophila model. Interestingly, overexpression of DP103 abrogated the effects of RX-5902, suggesting a requirement for RX-5902-mediated downregulation of DP103 to bring about anti-tumorigenic effects. Collectively, our data suggests a novel regulatory role for DP103 in the Wnt/β-catenin signaling pathway that is targetable by drugs like RX-5902.

Citation Format: Bunnag N, Yuan Y, Cai W, Suresh J, Young Bok L, Deog Joong K, Tolwinski N, Kumar AP. Characterization of a novel prognostic and targetable modulator of the Wnt/β-catenin signaling pathway in breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-15.
Abstract P6-20-17: Targeting SHP2 for the treatment of HER2-positive breast cancer
Authors: Agazie Y , Hartman Z
Published: May 2019

Approximately 20% of breast cancer (BC) is caused by overexpression of the human epidermal growth factor receptor 2 (HER2). As a result, several antibody-based and small molecule-based anti-HER2 therapies have been developed. These drugs have benefited BC patients by improving overall survival and quality of life. However, development of resistance and disease recurrence have been the major clinical challenges. One way to overcome these clinical problems is to develop alternative therapeutic strategies. Multiple lines of evidence show that targeting the Src homology phosphotyrosyl phosphatase 2 (SHP2) in HER2-positive BC may prove beneficial both in treatment-naïve and anti-HER2 therapy-resistant forms of the disease. For instance, silencing SHP2 expression in HER2-positive breast cancer cells or conditional knockout in ErbB2 transgenic mice blocks HER2 overexpression and associated signaling, leading to loss of cell transformation and tumorigenesis. To test the clinical translational significance of SHP2 targeting, we have invented a specific small molecule SHP2 inhibitor named WGMDY (US 9,932,288) that has shown promising anti-cancer effects. The results obtained so far show that inhibition of SHP2 with WGMDY blocks HER2 expression, suppresses cell proliferation and anchorage independent growth, and induces regression of preformed xenograft tumors. These findings suggest that SHP2 might be an excellent drug target for HER2-positive BC and WGMDY has a promising potential to serve as a lead compound for developing anti-SHP2 drugs.

Citation Format: Agazie Y, Hartman Z. Targeting SHP2 for the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-17.
Abstract PD2-04: Baseline circulating ESR1 mutation analysis in the randomised phase III EFECT study of fulvestrant versus exemestane in advanced hormone receptor positive breast cancer
Authors: Turner N , Swift C , Kilburn L , Garcia-Murillas I , Johnston S , Budzar A , Robertson J , Gradishar W , Piccart M , Schiavon G , Chia S
Published: May 2019

Background. ESR1 mutations are acquired frequently in hormone receptor positive breast cancer after treatment with aromatase inhibitors (AI) in the metastatic setting. In prior analysis of the SoFEA phase III randomised trial, we demonstrated the detection of ESR1 mutations in circulating tumor DNA (ctDNA) predicted for greater benefit of fulvestrant compared to exemestane (Fribbens et al JCO 2016).

Methods. The phase III EFECT study randomised 693 patients with ER+ metastatic breast cancer who had progressed on a prior non-steroidal AI, between fulvestrant loading dose and then 250mg q28 days and exemestane (Chia S, et al. J Clin Oncol 2008). Baseline serum samples were available from 227 patients in EFECT, and were analysed for the 8 most common ESR1 mutations by multiplex digital PCR. The association between baseline ESR1 status and time to progression (TTP) was analysed using Kaplan-Meier methods.

Results. ESR1 mutations were successfully analysed in 98% (222/227) of patients with baseline serum samples, with ESR1 mutations detected in 23.4% (52/222) samples. Overall, detection of ESR1 mutations at baseline was associated with shorter TTP (hazard ratio [HR] 2.03, 95% CI 1.26-3.29, p=0.004). In patients with ESR1 mutation detected, TTP was 2.0 months (95%CI, 1.7-2.4) on exemestane and 3.5 months (95%CI, 1.9-5.0) on fulvestrant (HR 0.67, 95%CI 0.37-1.19, p=0.17). In patients without ESR1 mutations detected, TTP was 4.5 months (95%CI, 3.7-5.6) on exemestane and 3.7 months (95%CI, 3.3-5.2) on fulvestrant (HR 1.05, 95%CI 0.75-1.45, p=0.78). A meta-analysis of SoFEA and EFECT will be presented at the conference.

Conclusions. Historical serum samples may be used for ctDNA analysis, illustrating the potential for future research of sample archives. Patients with ESR1 mutation detected in ctDNA have poor outcome when treated with exemestane, replicating prior results from SoFEA and demonstrating clinical utility for ESR1 mutation ctDNA analysis.

Citation Format: Turner N, Swift C, Kilburn L, Garcia-Murillas I, Johnston S, Budzar A, Robertson J, Gradishar W, Piccart M, Schiavon G, Chia S. Baseline circulating ESR1 mutation analysis in the randomised phase III EFECT study of fulvestrant versus exemestane in advanced hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD2-04.
Abstract PD7-01: Bromodomain protein 3 is a novel therapeutic target in invasive lobular carcinoma
Authors: Haley K , Walsh L , Moran B , Das S , Tarrant F , Caldas C , Bernards R , Gallagher W , O'Connor D , Ni Chonghaile T
Published: May 2019

Invasive lobular carcinoma (ILC) is a subtype of breast cancer comprising 10% of breast tumours. ILC is characterised by a loss of E-cadherin, and is generally estrogen receptor (ER) positive. The majority of ILC breast cancers are treated with endocrine therapy, although approximately one in three women are de novo resistant to therapy. To identify novel therapeutic targets for the treatment of ILC, we carried out RNA sequencing on 61 primary ILC samples. We found that high expression of the epigenetic reader, bromodomain protein 3 (BRD3) was associated with poor recurrence free survival. We also validated this finding in a separate cohort of 99 ILC patient samples using the METABRIC cohort. Next, we assessed ILC cell lines for sensitivity to JQ1, an inhibitor of BET family proteins. We found that JQ1 inhibited cell growth in all the cell lines tested. Interesting, two of the ILC cell lines were sensitive to JQ1-induced apoptosis, whereas two of the cell lines were inherently resistant to JQ1-induced apoptosis. Using dynamic BH3 profiling we showed that the JQ1 resistant cell lines were dependent on anti-apoptotic protein BCL-XL following JQ1 treatment. Interestingly, we show both in 2D and 3D cultures that JQ1 is synergistic when combined with the BH3 mimetic, ABT-263. Highlighting that combination treatment with JQ1 and ABT-263 may be a novel potential therapeutic option for ILC.

To unveil the mechanism underlying resistance to JQ1-induced apoptosis, we performed paired-end RNA sequencing and compared differentially expressed genes in JQ1 sensitive and JQ1 resistant ILC cell lines. DAVID gene ontology analysis identified 6 pathways differentially upregulated in the JQ1 resistant ILC cell line including MAPK, Wnt, and insulin resistance signaling. Interestingly, we found that ILC cell lines, which were resistant to BET inhibition with JQ1, demonstrated high levels of FGFR1-4 both at the mRNA level and the protein level. Combination treatment with JQ1 and the FGFR1 inhibitor PD173074 or following knockdown of FGFR with siRNA, resulted in increased cell death in JQ1 resistant cells. Currently, we are assessing how FGFR signaling enables survival of ILC cells following JQ1 treatment and determining the exact function of BRD3 in ILC. In conclusion, we have identified a novel therapeutic target, BRD3, which may be inhibited using JQ1 in combination with BH3 mimetic ABT-263 or FGFR1 inhibitor for a more effective treatment strategy for ILC.

Citation Format: Haley K, Walsh L, Moran B, Das S, Tarrant F, Caldas C, Bernards R, Gallagher W, O'Connor D, Ni Chonghaile T. Bromodomain protein 3 is a novel therapeutic target in invasive lobular carcinoma [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-01.
Abstract PD8-04: Neoadjuvant chemotherapy for breast cancer: Nodal downstaging is highly correlated with pathological complete response
Authors: Blumencranz P , Habibi M , Treece T , Blumencranz L , Yoder E , Audeh W , Carter E , McNaughton L , Roussos J , Shivers S , Acs G , Cox C , MINT Investigators Group
Published: May 2019

Background: Neoadjuvant chemotherapy (NAC) is employed in patients with larger tumors to attempt to downstage locally advanced cancers to allow breast conservation and to assess in vivo tumor response. The Multi-Institutional Neoadjuvant Therapy MammaPrint Project I (MINT) study asked a secondary question of whether complete nodal downstaging could also be achieved with NAC.

Methods: This analysis included 147 eligible invasive breast cancer patients with high tumor burdens, classified as cT2-4N0-3M0 (T2 greater than 3.5cm if N0). Patients who had a positive core biopsy and/or fine needle aspiration (FNA) on an axillary node prior to starting NAC were included in this analysis. Those who had a surgical sentinel lymph node biopsy were not included. Nodal involvement was established following neoadjuvant treatment by axillary lymph node dissection (ALND).

Results: This population was 54% postmenopausal, average age 53 yrs (range 25 to 80 yrs). Tumor characteristics were 91% invasive ductal carcinoma; 65% T2, 29% T3, 6% T4; 87% LN1, 13% LN2-3; 3% low grade, 38% intermediate grade, 59% high grade; 65% ER-positive, 49% PR-positive, and 28% HER2-positive by immunohistochemistry; 84% High Risk (HR) and 16% Low Risk (LR) by MammaPrint (MP). After NAC, 45% (66/147) of these LN-positive patients were down-staged to ypN0 and also achieved a complete pathological response in the primary tumor. The potential for down-staging was inversely-related to tumor burden, where 47% (60/128) of N1, 35% (6/17) of N2, and 0% (0/2) of N3 patients were down-staged to ypN0. There were 3 patients who were down-staged (2 N2 to N1, and 1 N3 to N2), but not to ypN0. At surgery, 34% (44/128) of patients had no change, and 19% (24/129) progressed in LN staging.

Pre vs Post NAC Nodal StagePre NAC Nodal StageypN0ypN1ypN2ypN3TotalcN16044222128cN2626317cN3  112Total6646296147

Conclusions: We confirmed that upon achieving a complete response of the primary tumor that there was also a pathologic complete response in the LN. About 53% of patients had no change or progression of LN involvement following NAC.

Citation Format: Blumencranz P, Habibi M, Treece T, Blumencranz L, Yoder E, Audeh W, Carter E, McNaughton L, Roussos J, Shivers S, Acs G, Cox C, MINT Investigators Group. Neoadjuvant chemotherapy for breast cancer: Nodal downstaging is highly correlated with pathological complete response [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-04.