advances in the management of breast cancer: highlights from the 2014 asco annual meeting

This activity is supported by independent educational grants from AstraZeneca Pharmaceuticals LP and Genentech.

EditorsKathy D. Miller, MDBallve’ Lantero Scholar in OncologyCo-Director of the IU Simon Cancer Center Breast Cancer ProgramAssociate Professor of MedicineDivision of Hematology/OncologyIU School of MedicineIndianapolis, Indiana

Joyce O’Shaughnessy, MDCo-Chair, Breast Cancer Research Program Celebrating Women Chair in Breast Cancer ResearchBaylor Charles A. Sammons Cancer CenterTexas OncologyUS OncologyDallas, Texas

Advances in the Management of Breast Cancer: Highlights from the 2014 ASCO Annual Meeting

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An Interactive PDF Newsletter


TABLE OF CONTENTS (CLICK THE SECTION YOU WISH TO VIEW)

INTRODUCTION ........................................................................................................................................ 1

HER2-TARGETED TREATMENTS ................................................................................................................ 1

The ALTTO Trial – Adjuvant Dual HER2 Inhibition .........................................................................................................1

CALBG 40601 – Gene Expression Signatures From a Neoadjuvant Trial ..................................................................3

Meta-Analysis of Adjuvant Trastuzumab Trials..............................................................................................................4

HORMONAL ISSUES IN PRE-MENOPAUSAL WOMEN .............................................................................. 5

IBCSG: TEXT and SOFT Trials ...............................................................................................................................................5

POEMS-S0230 ........................................................................................................................................................................7

HER2-NEGATIVE BREAST CANCER ......................................................................................................... 8

AROBASE – Maintenance Chemotherapy vs Hormone Therapy ................................................................................8

E5103 – Adjuvant Bevacizumab ........................................................................................................................................9

ARTemis – Bevacizumab With Neoadjuvant Chemotherapy ................................................................................... 10

BIOMARKERS FOR PLATINUM-BASED THERAPY .................................................................................. 10

GeparSixto: pCR and GermlineBRCA/Triple-Negative Breast Cancer .................................................................... 10

pCR as Predictor of Response in BRCA1/2 Triple-Negative Breast Cancer ............................................................ 11

TBCRC009 ............................................................................................................................................................................. 12

GeparSixto: Expression of Immunologic Genes .......................................................................................................... 13

BRE-146: RNA-Sequencing of Triple-Negative Breast Cancer .................................................................................. 14

CONCLUSION .......................................................................................................................................... 14

POST-TEST AND EVALUATION ................................................................................................................ 14

REFERENCES ............................................................................................................................................ 14

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MEDIA: NEWSLETTEREstimated time to complete activity: 1.0 hourRelease date: Friday, August 8, 2014 | Expiration date: Friday, August 7, 2015

INTRODUCTIONThe 2014 American Society of Clinical Oncology (ASCO) Annual Meeting held in Chicago, Illinois, provided a comprehensive review of key experimental and clinical data. Included in this newsletter are highlights from the conference covering major plenary sessions, key symposia, and targeted oral and poster presentations on the advances in the management of breast cancer.

EDITORSKathy D. Miller, MDBallve’ Lantero Scholar in OncologyCo-Director of the IU Simon Cancer Center Breast Cancer ProgramAssociate Professor of MedicineDivision of Hematology/OncologyIU School of MedicineIndianapolis, Indiana

TARGET AUDIENCE The target audience for this activity is medical oncologists, hematologist/oncologists, surgeons, radiation oncologists, pathologists, oncology pharmacists, and other allied healthcare professionals caring for patients with breast cancer.

EDUCATIONAL OBJECTIVESAt the conclusion of this activity, participants should be able to:

• Summarize the efficacy and safety results from key trials introducing use of novel agents and/or mechanisms • Select appropriate chemotherapy/biologic combination regimens based on current understanding of clinical markers, efficacy, and safety profiles • Describe advances in the development and integration of biologic therapies for the management of patients with breast cancer in novel disease settings

and combinations• Evaluate emerging new therapeutic options for treatment of breast cancer by reviewing ongoing and planned clinical trials

DESIGNATION OF CREDITPHYSICIAN CONTINUING EDUCATION Accreditation Statement

Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation Statement Educational Concepts Group, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

METHOD OF PARTICIPATIONThere are no fees for participating and receiving CME credit for this activity. During the period Friday, August 8, 2014 through Friday, August 7, 2015, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test and evaluation.

CME CREDITPhysicians who complete the post-test with a score of 80% or better may view and print their credit letter or statement of credit via the website, www.ecgcme.com.

Joyce O’Shaughnessy, MD Co-Chair, Breast Cancer Research Program Celebrating Women Chair in Breast Cancer ResearchBaylor Charles A. Sammons Cancer CenterTexas OncologyUS OncologyDallas, Texas

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POLICY ON DISCLOSUREIt is the policy of ECG that the faculty, authors, planners, and other persons who may influence content of this CME activity disclose all relevant financial relationships with commercial interests in order to allow ECG to identify and resolve any potential conflicts of interest.

The Following Faculty Members Have Declared Relevant Financial Relationships

Kathy D. Miller, MD Grants/Research Support Clovis Oncology, MacroGenics, Inc., Medivation, Inc., Merrimack Pharmaceuticals, Inc., Seattle Genetics, Inc., TAIHO PHARMACEUTICAL CO., LTD.

Joyce O’Shaughnessy, MD Consultant Fees Arno Therapeutics, Inc., Celgene Corporation, Corcept Therapeutics Inc., Eisai Inc., Genentech, GlaxoSmithKline, Johnson & Johnson Services, Inc., Lilly USA, LLC, med fusion, Merrimack Pharmaceuticals, Inc., Millennium: The Takeda Oncology Company, Novartis, Pfizer Inc, sanofi-aventis

STAFF DISCLOSUREPlanners and managers at ECG have no relevant financial relationships to disclose.

ACKNOWLEDGEMENTThe editors wish to thank Sara R. Fagerlie, PhD, CCMEP and Leonard Lionnet, PhD for assistance in writing this document.

DISCLOSURE OF OFF-LABEL USEThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. ECG does not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity do not necessarily represent the views of ECG. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Please refer to the official prescribing information for each product or consult the Physicians’ Desk Reference for discussion of approved indications, contraindications, and warnings.

ACKNOWLEDGEMENT OF COMMERCIAL SUPPORTThis activity is supported by independent educational grants from AstraZeneca Pharmaceuticals LP and Genentech.

CME INQUIRIESFor further information, please contact:Educational Concepts Group, LLC 1300 Parkwood Circle SE, Suite 325Atlanta, Georgia 30339Phone: 1.866.933.1681 | Fax: 1.866.933.1692www.ecgcme.com

None of the contents may be reproduced in any form without prior written permission from the publisher. This activity may be accessed at www.ecgcme.com.

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INTRODUCTIONBreast cancer is the most commonly diagnosed malignancy and the second leading cause of cancer mortality among women.1 Despite extraordinary innovations and progress, improvements in longevity and quality of life (QoL), unmet needs still remain. In women with early-stage breast cancer, upwards of 30% will develop distant metastases within 5 years of initial diagnosis and 20% will develop recurrence over 10 years following adjuvant systemic treatment.2-4 Approximately 5-10% and 32% of all women have regional or metastatic breast cancer (MBC) at the time of initial diagnosis, respectively.5 Moreover, MBC is incurable, with a 5-year survival of approximately 24.3%.6

Experts worldwide gathered in Chicago, Illinois for the 2014 American Society of Clinical Oncology’s (ASCO) Annual Meeting where a wealth of data and information was presented on the evolving landscape of breast cancer treatment, one which has evolved from an era of stage-centered treatment to tumor-centered treatment. Highlights from the conference focusing on targeted treatments for early and metastatic breast cancers as well as biomarkers for intervention are presented in this newsletter.

HER2-TARGETED TREATMENTSThe ALTTO Trial – Adjuvant Dual HER2 InhibitionDual HER2 blockade using lapatinib and trastuzumab or pertuzumab and trastuzumab compared with single HER2 blockade has resulted in increased progression-free survival (PFS) and overall survival (OS) in advanced disease and significant pathologic complete response (pCR) in the neoadjuvant setting. However, until now, dual HER2 blockade has not been assessed in the adjuvant setting.7

Dr Martine Piccart-Gebhart presented the first results from the phase III, randomized, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial (BIG 02-06; NCCTG 063D), which compared 1 year of anti-HER2 treatment with lapatinib alone, trastuzumab alone, their sequence, or combination in the adjuvant treatment of early breast cancer.

From June 2007 to July 2011, patients were randomized from 946 sites in 44 countries to receive either lapatinib and trastuzumab, trastuzumab followed by lapatinib (trastuzumab→lapatinib), and lapatinib or trastuzumab alone. Three treatment strategies were employed: 1) sequential anti-HER2 treatment after chemotherapy (N = 4613), (Figure 1), 2) concurrent anti-HER2 therapy after anthracycline-based chemotherapy (N = 3337), 3) concurrent

anti-HER2 treatments with a non-anthracycline, taxane, and platinum-containing chemotherapy (N = 431). There was a lower than expected delivered dose of lapatinib in combination with trastuzumab due to toxicity. The lapatinib arm was closed in August 2011 for futility and is not presented.

Figure 1. Design of the phase III ALTTO trial.

3-weekly trastuzumab

Lapatinib*

Lapatinib

Lapatinib + 3-weekly trastuzumab

Weekly trastuzumab

Washout

All (neo)adjuvant CT prior to anti-HER2 therapy

12 weeks 6 wks 34 wks

52 weeks

All patients: radiotherapy, if indicated (concomitant with targeted therapy).Hormone receptor positive patients: endocrine therapy for at least 5 years.*The L alone arm was closed on 18 Aug, 2011 following IDMC recommendation

Tras alone: 8 mg/kg → 6mg/kg IV, q21 daysLap alone: 1500 mg po qdTras → Lap: T 4 mg/kg → 2 mg/kg IV, q7 days: L 1500 mg po qdTras → Lap: T 8 mg/kg → 6mg/kg IV, q21 days: L 1500 mg po qd

Lap, lapatinib; Tras, trastuzumab

(N = 4613)

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The primary endpoint was invasive disease-free survival (DFS) defined as first occurrence of breast cancer at any site, second primary cancer (invasive contralateral breast cancer or non-breast malignancy), or death from any cause as first event. Secondary endpoints included OS and safety (general and cardiac safety). Lapatinib and trastuzumab vs trastuzumab alone was tested for superiority and trastuzumab followed by lapatinib vs trastuzumab alone was tested for non-inferiority (1.11 margin with a P value ≤ 0.025 required for statistical significance). The current analysis was planned after 850 DFS events in the lapatinib and trastuzumab vs trastuzumab alone (required to detect a hazard ratio [HR] of 0.80 with experiment-wide alpha = 0.05) or at 4.5-year median follow up (MFU).

Excluding patients from the lapatinib alone arm, 6,281 patients were randomized. Patient and disease characteristics were well balanced; 40% were node-negative and 57% were hormone-receptor-positive (HR+). Only 555 DFS events for the lapatinib and trastuzumab vs trastuzumab comparison were observed at 4.5 years MFU. The hazard ratio (HR) for DFS was 0.84 (4-year DFS, 88% vs 86%) for lapatinib and trastuzumab vs trastuzumab and 0.93 (4-year DFS rate 87% vs 86%) for trastuzumab→ lapatinib vs trastuzumab (Table 1). The HR for OS, was 0.80 (4-year OS rate 95% vs 94%) for the lapatinib and trastuzumab vs trastuzumab comparison and 0.91 (4-year OS, 95% vs 94% rate) for the trastuzumab→lapatinib vs trastuzumab comparison.

Diarrhea (75% and 50% vs 20%), rash (55% and 49% vs 20%), and hepatobiliary (23% and 24% vs 16%) adverse events (AEs) were more frequent in the lapatinib and trastuzumab and lapatinib → trastuzumab treatment arms, respectively, compared to the trastuzumab alone study arm (P < 0.001 for all arms compared to trastuzumab). Primary cardiac endpoints were infrequent (< 1%) in all arms. While cardiac toxicity remained low in all treatment arms, lapatinib was associated with significant increase in AEs of special interest compared with trastuzumab alone (ie, diarrhea, hepatobiliary, and rash or erythema).

The ALTTO trial did not meet its primary endpoint (DFS) as neither the lapatinib and trastuzumab vs trastuzumab comparison nor the trastuzumab→lapatinib vs trastuzumab comparison yielded required statistical significance. The doubling in pCR observed with lapatinib and trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in ALTTO at 4.5 years MFU. Dual HER2 blockade does not provide a benefit in the adjuvant setting.

Table 1. ALTTO: Disease-free survival and overall survival.

Lapatinib + Trastuzumab Trastuzumab → Lapatinib Trastuzumab

n = 2093 n = 2091 n = 2097

DFS events 254 284 301

4-year DFS 88% 87% 86%

HR* (95% CI), P* 0.84 (0.70, 1.02), 0.048 0.96 (0.80, 1.15), 0.610

OS events 106 119 135

4-year OS 95% 95% 94%

HR* (95% CI), P* 0.80 (0.62, 1.03), 0.078 0.91 (0.71, 1.16), 0.433

*vs trastuzumab. P value ≤ 0.025 required for statistical significance. DFS, disease-free survival; OS, overall survival; HR, hazard ratio.

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CALBG 40601 – Gene Expression Signatures From a Neoadjuvant TrialDr Lisa A Carey presented first results of gene expression signatures analysis in pre- and post-therapy treatment specimens from the CALGB 40601 (Alliance) study, a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2+ breast cancer (Figure 2).8

The correlative endpoints for the present analysis examined RNA-based signatures as predictive biomarkers for response to HER2-directed therapy in pre-therapy specimens and to investigate biology of residual disease and potential resistance mechanisms in matched pre- and post-therapy specimens. Gene expression by mRNA sequencing (RNAseq) was performed on 265 pre-treatment and 78 matched post-treatment samples. RNAseq was normalized to the breast data set in The Cancer Genome Atlas Project and gene expression signatures included:

• Intrinsic subtype • Proliferation• Immune cell features• P53 mutant signature

In this analysis, 60% of pre-treatment specimens were HR+. Rates of in-breast pCR from the primary analysis for dual therapy (trastuzumab + paclitaxel + lapatinib) versus single (trastuzumab + paclitaxel) were 56% and 46%, (P = 0.12), respectively.9 Overall, intrinsic subtypes in untreated HER2+ disease (n = 265) were: 30% Luminal A, 30% Luminal B, 31% HER2-Enriched, 6% Basal-like, 2% Normal-like, and 1% Claudin-Low. In-breast pCR was 46%, which varied significantly by subtype: HER2-Enriched 70% compared with Luminal A 34%, Luminal B 36%, and Basal-Like 36% (P < 0.04) (Figure 3). The most frequent subtype change among non-normal-like samples (n = 55) was to the Luminal A subtype, which occurred in 70% of baseline Luminal B, and 67% of HER2-Enriched tumors. Most (87%) had decreased proliferation scores (P < 0.0001). Pathologic CR rates were numerically greater for HER2-enriched patients in the paclitaxel + trastuzumab + lapatinib (80%), paclitaxel + trastuzumab (71%), and trastuzumab + lapatinib (52%) treatment arms.

Figure 2. Trial schema for CALGB 40601.

RANDOMIZED

AC = anthracycline-containing; Lap = lapatinib; Pac = paclitaxel; Tras = trastuzumab; w = weekly

Recommended:Dose-dense AC to

Tras x 34 wks

Clinical stage 2-3HER2+ Breast

Cancer

SURGERY

Research Tissue

Research Tissue

wPac + Tras 16 wk

wPac + Lap 16 wk

wPac + Tras + Lap 16 wk

Figure 3. Pathologic complete response in CALGB 40601 by intrinsic subtype.

70

8071

52

34 37 38

9

3640 41

22

0

10

20

30

40

50

60

70

80

90

100

Overall Pac + Tras + Lap Pac + Tras Pac + Lap

HER2E (n = 82) Luminal A (n = 80) Luminal B (n = 80)

P = 0.04

Perc

enta

ge

Pac, paclitaxel; tras, trastuzumab; lap, lapatinib

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Pathologic CR rates by 11-gene proliferation signature were significant: high 53%, intermediate 43%, and low 30% (P = 0.005), but there was no evidence of interaction by treatment arm (Figure 4).

High expression of immune signatures, especially B-cell related, were significantly associated with pCR (IgG signature high 61%, intermediate 39%, low 31%; P < 0.001). In multivariable analysis, treatment (paclitaxel + trastuzumab + lapatinib vs paclitaxel + trastuzumab), intrinsic subtype (HER2-enriched vs not), IgG signature, proliferation signature, and P53 mutation signature were all significant predictors of pCR (P = 0.02) (Table 2).

In addition to treatment, genomics (intrinsic subtype, proliferation), genetics (P53 mutation), and microenvironment (immune cells) contributed to response. Benefit of dual HER2-targeting appeared limited to the HER2-enriched subtype; however, there was a very high pCR rate across all arms in HER2-enriched tumors. There was a shift towards Luminal A intrinsic subtype in residual disease; this may reflect increased stroma, decreased proliferation, intratumoral heterogeneity, and/or decreased HER2 signaling. Confirmation of these findings will require a pooled analysis in a far larger dataset.

Meta-Analysis of Adjuvant Trastuzumab Trials Dr Ciara O’Sullivan reported meta-analysis results from multiple trials where the effects of adjuvant trastuzumab were assessed in HER2+/- patients with tumors ≤ 2 cm.10 There, patients with tumors ≤ 2 cm (T1a, T1b, T1c; 0-1, 2-3 and ≥ 4 positive nodes) who received trastuzumab benefited significantly in terms of DFS (8-year gain in HER2+ of 7%, P < 0.001 and in HER2- 9.4%; P < 0.0001) and OS (8-year gain in HER2+ of 3.8%, P = 0.005 and in HER2- 8.8% P = 0.0001).

Figure 4. Pathologic complete response by 11-gene proliferation signature in CALGB 40601.

53

66

494243

48 49

21

3035

28 25

0

10

20

30

40

50

60

70

80

90

100

Overall Pac + Tras + Lap Pac + Tras + Lap Tras + Lap

High (n = 118) Intermediate (n = 104) Low (n = 43)

P = 0.005

Lap, lapatinib; pac, paclitaxel; tras, trastuzumab

Perc

enta

ge

Table 2. CALBG 40601: predictors of pCR (multivariate analysis*).

Variable Contrast OR P Value

Treatment Pac + Tras + Lap vs Pac + Tras 1.38 0.003

Pac + Lap vs Pac + Tras 0.36 0.003

Intrinsic subtype HER2-E vs not 2.96 0.002

IgG signature 1-unit change 1.56 0.002

11-gene proliferation signature 1-unit change 0.50 0.021

P53 mutation signature 1-unit change 3.32 < 0.001

HER2-E, HER2-enriched; Lap, lapatinib; OR, odds ratio; Pac, paclitaxel; Tras, trastuzumab. *Logistic regression model using forward-selection from base model of treatment arm; all terms with P < 0.05 included in the final model.

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HORMONAL ISSUES IN PRE-MENOPAUSAL WOMENIBCSG: TEXT and SOFT TrialsWhile adjuvant endocrine therapy with aromatase inhibitor improves outcomes compared to tamoxifen in women with post-menopausal HR+ breast cancer, the optimal adjuvant endocrine therapy for pre-menopausal women with HR+ is unclear.11 Currently, tamoxifen for ≥ 5 years is a standard of care. Ovarian function suppression (OFS) may also be given. The International Breast Cancer Study Group (IBCSG) designed the Tamoxifen and EXemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) trials to determine whether adjuvant aromatase inhibitor improved outcomes in pre-menopausal women with HR+ breast cancer treated with OFS and to determine the value of ovarian function in women who remain pre-menopausal and are suitable for adjuvant tamoxifen.

Dr Olivia Pagani presented results from a joint analysis of IBCSG’s TEXT and SOFT trials where treatment with an adjuvant aromatase inhibitor, exemestane, plus OFS were compared with tamoxifen plus OFS in pre-menopausal women with HR+ early breast cancer.

TEXT and SOFT were randomized phase III trials where 5,738 pre-menopausal women with HR+ early breast cancer were enrolled from November 2003 to April 2011 (TEXT n = 2672; SOFT n = 3066) (Figure 5). In TEXT, women who were at least 12 weeks post-surgery were randomized to 5 years of exemestane with OFS or tamoxifen with OFS; chemotherapy was optional and concurrent with OFS. In SOFT, women who were either more than 12 weeks post-surgery if no chemotherapy was planned or 8 months of completing (neo)adjuvant chemotherapy were randomized to 5 years of exemestane with OFS or tamoxifen with OFS vs tamoxifen alone. Ovarian function suppression was by choice of 5-year triptorelin, oophorectomy, or ovarian irradiation. Eligibility criteria are included in Figure 5.

The primary endpoint was DFS (randomization until invasive local, regional, distant recurrence, or contralateral breast; 2nd malignancy or death). Secondary endpoints included breast cancer-free interval (BCFI; invasive recurrence or contralateral breast cancer), distant recurrence-free interval (DRFI), and OS. Due to low event rates, protocol amendments in 2011 changed the analysis plans to answer the aromatase inhibitor question (exemestane + OFS vs tamoxifen + OFS) by joint analysis of TEXT and SOFT. By Q3 of 2013 with > 5-year median follow-up, 436 DFS events were projected, providing 84% power for HR, 0.75 with exemestane + OFS vs tamoxifen + OFS (stratified log-rank 2-sided α,0.05).

Figure 5. Schema for the TEXT and SOFT trials.

Joint Analysis (N = 4690)

Tamoxifen + OFS x 5 years

Exemestane + OFS x 5 years

RANDOMIZED

OFS, ovarian function suppression; CT, chemotherapy

RANDOMIZED

• Pre-menopausal• ≤ 12 weeks after surgery• Planned OFS• No planned CT• OR planned CT

OR

TEXT

SOFTTamoxifen x 5 years





• Pre-menopausal• ≤ 12 weeks after surgery• No CT

• Remained pre-menopausal ≤ 8 m after CT

Median follow-up 5.7 years

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At 5.7 years median follow-up, 514 (11%) DFS events were reported in the ITT population comparing exemestane and OFS (n = 2346) to tamoxifen and OFS (n = 2344). Patients assigned to exemestane and OFS had significantly reduced DFS hazard (HR = 0.72; 95% CI, 0.60-0.86; P = 0.0002) compared to tamoxifen and OFS. The 5-year DFS was 91.1% vs 87.3% (Figure 6).

Reductions were similar for the secondary endpoints of BCFI (HR = 0.66 [0.55-0.80]), 5-year BCFI (92.8% vs 88.8%) and DRFI (HR = 0.78 [0.62-0.97]), though not OS (HR = 1.14 [0.86-1.51]) at this early follow-up (194 [4%] deaths) (Figure 7).

Figure 6. Disease-free survival in TEXT and SOFT.

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4 52 310 6

Perc

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E + OFST + OFS

216298

0.72 0.60 - 0.85 0.0002Events HR 95% CI P

Exemestane + OFS (n = 2346) Tamoxifen + OFS (n = 2344)

Difference 3.8% at 5 years

87.3%

5-yr DFS91.1%

No. PatientsE+OFS T+OFS

2346

526470806544

1362984

All Patients

Cohort

Lymph Node Status

No chemotherapy, TEXTNo chemotherapy, SOFTChemotherapy, TEXTPrior chemotherapy, SOFT

NegativePositive

2344

527473801543

1350994

5-yr DFS %HR (95% CI)E+OFS T+OFS

91.1

96.195.889.884.3

95.185.6

87.3

93.093.184.680.6

91.681.4

.25 .50 .72 1.0 2.0 4.0

Favors E+OFS Favors T+OFS

OFS, ovarian function suppression; E, exemestane; T, tamoxifen; HR, hazard ratio; DFS, disease-free survival

Figure 7. Outcomes in the TEXT and SOFT trials: (A) breast cancer-free interval (B) distant recurrence-free interval (C) overall survival.

A. B. C. 100

60

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4 52 310 6Years Since Randomization

E + OFST + OFS

175262

0.66 0.55 - 0.80 < 0.0001Events HR 95% CI P

Exemestane+OFS (N = 2346) Tamoxifen+OFS (N = 2344)

88.8%

5-yr BCFI92.8%

Perc

ent W

ithou

t Bre

ast C

ance

r 100

60

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E + OFST + OFS

142183

0.78 0.62 - 0.97 < 0.02Events HR 95% CI P

92.0%

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Perc

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nce 100

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1.14 0.86 - 1.51 0.37Events HR 95% CI P

95.9%

5-yr OS96.9%

Perc

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live

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Adverse event profiles were comparable with post-menopausal women; Grade 3-4 targeted AEs were reported in 31% exemestane + OFS and 29% tamoxifen + OFS patients. Early cessation of all assigned treatments was more frequent with exemestane + OFS. The side effect profile of exemestane + OFS is consistent with that observed with aromatase inhibitors in post-menopausal women.

In pre-menopausal women with HR+ breast cancer, adjuvant treatment with exemestane + OFS significantly improved DFS, BCFI, and DRFI and could be considered a new treatment option for women with HR+ early breast cancer. However, caution should be taken considering the toxicity associated with treatment combining OFS plus an aromatase inhibitor, the impact of OFS in pre-menopausal women has yet to be determined. Notably, in the ABCSG-12 trial which assessed the efficacy of ovarian suppression using goserelin combined with anastrozole or tamoxifen ± zoledronic acid in ER+ breast cancer, there was no significant difference in DFS between anastrozole + goserelin and tamoxifen + goserelin at median follow-up of 62 months.12

POEMS-S0230 Ovarian failure is a common consequence of chemotherapy treatment and is dependent upon chemotherapy regimen/duration, patient age, and gonadal activity at the time of chemotherapy administration. Results from randomized studies in breast cancer have been mixed and have commonly used return of menses as an endpoint.

The phase III study, Prevention Of Early Menopause Study (POEMS)-S0230 (an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB [Alliance]), assessed the reduction of ovarian failure in patients with early-stage, HR- breast cancer receiving LHRH analog treatment (goserelin) during chemotherapy, was presented by Moore et al.13

POEMS is the largest randomized study of LHRH agonist treatment for ovarian protection addressing 2-year endpoints. Pre-menopausal patients over 50 years with stage I-IIIA ER/PR-negative breast cancer to be treated with chemotherapy were randomized to receive standard cyclophosphamide-containing chemotherapy with or without monthly goserelin 3.6 mg SQ starting 1 week prior to the first chemotherapy dose. The primary endpoint was 2-year premature ovarian failure, defined as amenorrhea for the prior 6 months and post-menopausal levels of follicle stimulating hormone (FSH). Other endpoints include pregnancies and survival. Endpoints were analyzed in multivariable regression adjusting for stratification factors (age and chemotherapy regimen).

Among 218 evaluable patients, 62% had complete primary endpoint data. Dropouts (n = 83) were mostly due to deaths (n = 14) or lack of FSH data. There was no strong evidence of informative missing data by arm according to stratification factors (P > 0.05). Premature ovarian failure rates were 22% in the standard arm and 8% in the goserelin arm (OR = 0.30, 95% CI: 0.10-0.87, P = 0.03 [univariate analysis]; OR = 0.30, 95% CI 0.09-0.97, P = 0.04 (stratified analysis accounting for age and regimen; and OR = 0.36, 95% CI: 0.11-1.14, P = 0.08 [multivariate analysis]) (Table 3).

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In a sensitivity analysis defining 2-year premature ovarian failure more liberally as either amenorrhea or elevated FSH, 45% in the standard arm and 20% in the goserelin arm had premature ovarian failure (OR = 0.29, 95% CI: 0.12-0.70, P = 0.006). There were 13 pregnancies in the standard arm and 22 in the goserelin arm (OR = 2.22, 95% CI: 1.00-4.92, P = 0.05). Disease-free survival and OS were greater in the goserelin arm (Cox regression, including stage: HR = 0.49, 95% CI: 0.24-0.97, P = 0.04; HR = 0.43, 95% CI: 0.18-1.00, P = 0.05, respectively) (Figure 8A-8B).

In pre-menopausal patients under the age of 50 years with stage I-IIIA ER/PR-negative breast cancer, LHRH analog administration with chemotherapy was associated with less premature ovarian failure and more pregnancies. Results presented here for the POEMS trial are the first to demonstrate improved fertility prospects and more successful pregnancies in this patient population. In an exploratory analysis, goserelin use in pre-menopausal ER-negative breast cancer was associated with improved DFS and OS.

HER2-NEGATIVE BREAST CANCERAROBASE – Maintenance Chemotherapy vs Hormone TherapyWhile endocrine therapy combined with bevacizumab has been proven tolerable and may be an option as maintenance therapy after paclitaxel and bevacizumab, there is no prospective evidence for maintenance endocrine therapy after chemotherapy as a therapeutic option in the metastatic setting. In addition, given the risk of taxane discontinuation due to AEs, maintenance strategies with endocrine therapy plus bevacizumab may improve PFS and may reduce chemotherapy toxicities.

Dr Olivier Tredan presented data from AROBASE, a prospective, randomized, open label, phase III study, randomizing patients with histologically confirmed ER+ HER2- locally advanced or MBC, who had not progressed after 16-24 weeks of first-line paclitaxel with bevacizumab therapy, to paclitaxel with bevacizumab continuation or endocrine therapy with bevacizumab (exemestane 25 mg/day with bevacizumab 15 mg/kg q3w) (Figure 9).14

Table 3. POEMS premature ovarian failure rates.Standard Chemotherapy Chemotherapy

+ Goserelin

Ovarian failure at 2 years 15/68 = 22% 5/66 = 8%

Logistic Regression Results

Univariate, OR (95% CI)1-sided, 2-sided P

0.30 (0.10-0.87)0.01, 0.03

Stratified,* OR (95% CI)1-sided, 2-sided P

0.30 (0.09-0.97)0.02, 0.04

Multivariate,* OR (95% CI)1-sided, 2-sided P

0.36 (0.11-1.14)0.04, 0.08

*Accounting for age and regimen through stratification or covariate adjustment, respectively. OR, odds ratio.

Figure 8. (A) Disease Free and (B) Overall Survival in the POEMS trial.

100%

60%

20%

0%

40%

80%

4 52 310 6

Perc

ent A

live

and

Dis

ease

-Fre

e

Years From Randomization

GoserelinStandard

105113

1224

89%78%

At RiskRelapseor Death

4-YearEstimate

Goserelin

StandardRegressionCovariates

HR (95% CI)P value

Adjusted for ageand regimen

0.47 (0.24-0.95)P = 0.04

Adjusted for age,regimen, & stage

0.49 (0.24-0.97)P = 0.04

100%

60%

20%

0%

40%

80%

4 52 310 6

Perc

ent A

live

Years From Randomization

GoserelinStandard

105113

817

92%82%

At Risk Deaths4-Year

Estimate

Goserelin

Standard RegressionCovariates

HR (95% CI)P value

Adjusted for ageand regimen

0.45 (0.19-1.04)P = 0.06

Adjusted for age,regimen, & stage

0.43 (0.18-1.00)P = 0.05

A.

B.

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The primary endpoint of the study was PFS; secondary endpoints were OS, time to progression from beginning of treatment, safety/tolerability, and QoL. Kaplan-Meier estimates were used to calculate all time-to-event endpoints. Log-rank test was used for comparison for all time-to-events endpoints between treatment arms.

At the cut-off date for the interim analysis, 117 patients were included (n = 58 for exemestane + bevacizumab; n = 59 for paclitaxel + bevacizumab), 98 were analyzable. Median patient age was 55-56 years (range 35-86 years). Patients in the exemestane + bevacizumab and paclitaxel + bevacizumab treatment groups received prior endocrine therapy in the adjuvant (58% vs 66%) and metastatic (21% and 30%) settings.

With a median follow-up of 21 months (range 0.8-43.1), PFS was 7.6 months (95% CI 5.4-10.9; HR 1.0; P = 0.998) for exemestane + bevacizumab and 8.1 months (95% CI 6.5-10.7; HR 1.00; P = 0.998) for paclitaxel + bevacizumab (Table 4). The 6-month PFS rate was 55% (95% CI 42-67) and 67% (95% CI 54-78) for both groups.

Grade 3-4 AEs rates were generally lower with exemestane + bevacizumab (fatigue: 5% of patients vs 14%; neuropathy: 0% vs 12%; anemia: 0 vs 5%; pain: 2% vs 8%; neutropenia: 0% vs 12%), as well as serious AEs related to treatment (overall: 17% vs 31%). Deaths were reported for 19 (33%) and 16 (27%) patients in the exemestane + bevacizumab and paclitaxel + bevacizumab arm; median OS was not reached. No differences were detected between treatment groups with respect to EORTC QLQ-C30 QoL scores.

The study failed to show superiority of exemestane + bevacizumab compared with paclitaxel + bevacizumab; however, the exemestane + bevacizumab arm had a more favorable toxicity profile. Based on both safety and efficacy results, the IDMC stopped further enrollment.

E5103 – Adjuvant BevacizumabIn the E5103 trial, reported by Dr Kathy Miller, a double-blind phase III trial of doxorubicin and cyclophosphamide followed by paclitaxel with bevacizumab or placebo in patients with lymph node-positive and high-risk lymph node-negative breast cancer, bevacizumab in the adjuvant setting did not improve DFS.15 Five-year IDFS rates were 77% (arm a: anthracycline→paclitaxel), 76% (arm b: anthracycline + bevacizumab→paclitaxel + bevacizumab), and 80% (arm c: anthracycline + bevacizumab→bevacizumab + paclitaxel→bevacizumab; HR = 0.87 [0.70-1.08]; P = 0.17).

Table 4. AROBASE: progression-free survival.Exemestane + Bevacizumab (n = 58) Paclitaxel + Bevacizumab (n = 59)

PFS, median, m 7.6 8.1

Censored, n, % 14 (24) 11 (19)

Events, n, % 44 (76) 48 (81)

95% CI 5.4-10.8 6.5-10.7

HR 1.00 (0.66-1.51)

P Value P = 0.998

E, exemestane; T, taxane; HR, hazard ratio; PFS, progression-free survival.

Figure 9. Design of the AROBASE trial.

No evidence of disease

progression

Taxane+

Bevacizumab

First-Line CT

Taxane + Bevacizumab continuation

16-24 weeks

Maintenance until progression or toxicity

Exemestane (25 mg/d)+

BEV (15 mg/kg q3w)

R

First -Line CT• Taxane

• Paclitaxel: 80-90 mg/m2 for 3 weeks/4-week cycle• Docetaxel: 75 mg/m2 q3w

• Bevacizumab• 10 mg/kg q2w or 15 mg/kg q3w

Stratification• Investigational site• Previous exposure to aromatase inhibitors• Previous low hormone treatment sensitivity• Menopausal status

BEV, bevacizumab; CT, chemotherapy

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ARTemis – Bevacizumab With Neoadjuvant ChemotherapyReported by Dr Helena Margaret Earl, in the ARTemis trial, a randomized trial of bevacizumab with neoadjuvant chemotherapy (NACT) for patients with HER2- early breast cancer, significantly more patients on bevacizumab + (NACT, docetaxel [D], 5-flourouracil, epirubicin, and cyclophosphamide [FEC] had a pCR (22% (18-27%) vs 17% (13-21%) with D-FEC; P = 0.03 [adjusted for stratification factors]).16 Pathologic CR rates differed significantly across ER groups (negative 38%, weak positive 39%, strong positive 7%; P < 0.0001). The treatment effect of bevacizumab remained significant after adjustment for ER (P = 0.03). Overall, ARTemis showed a significant improvement in pCR with the addition of bevacizumab to D-FEC. ER-negative and ER-weak positive/HER2- breast cancer patients appeared to benefit most from bevacizumab, while pCR rates in ER-strong positive patients were lower and did not appear to show improvement from the addition of bevacizumab.

BIOMARKERS FOR PLATINUM-BASED THERAPYGeparSixto: pCR and GermlineBRCA/Triple-Negative Breast CancerCohort studies suggest high sensitivity to the DNA-damaging agents, cisplatin or carboplatin, in triple-negative breast cancer or in patients with BRCA mutations. Phase II studies (CALGB 40603, GeparSixto) found that the rate of pCR was higher when carboplatin was added to anthracycline/taxane-based chemotherapy. At the 2013 ASCO Annual Meeting, results from the randomized, neoadjuvant phase II GeparSixto study in patients with triple-negative breast cancer demonstrated that the addition of carboplatin substantially improved the pCR rates from 36.9% with weekly paclitaxel/non-pegylated liposomal doxorubicin to 53.2% with weekly paclitaxel/non-pegylated liposomal doxorubicin combined with weekly carboplatin.17 At the 2014 ASCO Annual Meeting, Dr Gunter Von Minckwitz presented analysis of the triple-negative subset of the GeparSixto trial on correlation between the pCR and germline breast cancer mutation (gBRCA) and/or family history for breast or ovarian cancer (Figure 10).18

Full blood samples with sufficient amount of DNA were available in 294/595 patients with triple-negative breast cancer from GeparSixto. gBRCA mutations were ascertained by MLPA and Fluidigm screening for recurrent pathogenic BRCA1/2 alterations. In combination, both methods enable us to detect approximately 60% of all expected mutation carriers. Pathologic CR rates with/without carboplatin were the primary endpoint of the analysis. Pathologic CR was defined conservatively as the absence of invasive cancer and in-situ cancer in both the breast and axillary nodes (ypT0 ypN0). Secondary endpoints were to correlate germline BRCA alteration and family history for breast and ovarian cancer with pCR in patients with triple-negative breast cancer.

Figure 10. GeparSixto trial design: patients in the triple-negative breast cancer subgroup.

RANDOMIZED

Paclitaxel 80 mg/m2 q1w

Carboplatin AUC 1.5-2.0 q1w

SURGERY

Non-pegylated liposomal doxorubicin 20 mg/m2 q1w

Bevacizumab 15 mg/kg q3w

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A total of 44 mutation carriers with gBRCA/RAD alterations and 250 without such alteration were identified. Patient groups were balanced with respect to age, median tumor size, family history for breast or ovarian cancer, and gBRCA alterations. Pathologic CR rates (ypT0 ypN0) in all patients with triple-negative breast cancer were 63.6% (n = 14/22) and 40.4% (n = 69/171) for patients with and without a family history for breast or ovarian cancer and gBRCA/RAD alteration (Table 5). Using a more commonly used pCR definition, which included DCIS cases (ypT0/is ypN0), pCR rates for patients with and without a family history for breast/ovarian cancer and gBRCA/RAD alterations, were 81.8% (18/22), and 43.9% (75/171).

Increase of pCR rates by carboplatin use was highest in patients with family history of breast or ovarian cancer (26%; P = 0.02) and alterations of gBRCA/RAD (23%; P = 0.13). Without risk factors, pCR gain with carboplatin use was only marginal (11%) (Table 6).

From these data, the authors concluded that 1) gBRCA mutation and family history were predictors for higher pCR rates after neoadjuvant anthracycline/taxane-based chemotherapy in triple-negative breast cancer, 2) that the additive effect of carboplatin was most prominent in patients with gBRCA mutation, 3) germline mutation status and family history for breast/ovarian cancer might assist in identifying patients who would benefit from carboplatin as part of neoadjuvant chemotherapy and justify the associated increased in toxicity.

pCR as Predictor of Response in BRCA1/2 Triple-Negative Breast CancerIn a related analysis, Dr Paluch-Shimon presented data from a study that assessed pCR as a predictor for outcomes in BRCA mutation carriers with triple-negative breast cancer.19 From a prospective neoadjuvant database of 588 breast cancer cases, 80 triple-negative patients who had undergone BRCA genotyping and received dose-dense chemotherapy with an anthracycline and a taxane were identified. Authors found significantly greater chemosensitivity in BRCA1/2 associated triple-negative breast cancer compared

Table 5. GeparSixto: pCR rates in all patients with triple-negative breast cancer.

pCR (ypT0 ypN0)gBRCA/RAD Alteration

pCR (ypT0/is ypN0)gBRCA/RAD Alteration

Family History n No Yes n No Yes

n = 250 n = 44 n = 250 n = 44

No, % (n/N) 193 40.4% (69/171) 45.5% (10/22) 193 43.9% (75/171) 45.5% (10/22)

Yes, % (n/N) 101 44.3% (35/79) 63.6% (14/22) 101 49.4% (39/79) 81.8% (18/22)

Table 6. GeparSixto: prediction of carboplatin effect on pCR.

Pac + Dox + Bev(n = 146)

Pac + Dox + Bev + Carb(n = 149) OR P Value

No risk factor 34.5% 46.0% 1.61 0.13

Family history of breast or ovarian cancer 30.8% 57.5% 3.04 0.02

gBRCA/RAD alteration with/without family history 43.5% 66.7% 2.60 0.13

Bev, bevacizumab; Carb, carboplatin; Dox, non-pegylated liposomal doxorubicin; OR, odds ratio; Pac, paclitaxel.



with non-BRCA as demonstrated by superior pCR. Importantly, pCR in patients with triple-negative breast cancer was not a surrogate for relapse-free survival in BRCA1/2 as opposed to non-BRCA1/2 carriers. The chemosensitivity in BRCA-associated triple-negative breast cancer may have increased the mutational spectrum in tumors due to predisposition to DNA breaks, resulting in selection of more aggressive, metastases prone clones.

TBCRC009Triple-negative breast cancer has a poor prognosis compared to other breast cancer subtypes and lacks therapeutic targets. Platinum chemotherapy has shown activity in triple-negative breast cancer and has a particular effect in BRCA-associated breast cancer. To date, there are no biomarkers in sporadic triple-negative breast cancer that correlate with BRCA-like phenotype of platinum treatment response.

Dr Steve Isakoff presented correlative biomarker data from TBCRC009, a single-arm, multicenter phase II study evaluating platinum monotherapy in first- or second-line treatment of metastatic triple-negative breast cancer. Authors sought to identify biomarkers to predict response to single-agent platinum chemotherapy in metastatic triple-negative breast cancer.20

Participants had measurable disease, available archival tumor, ≤ 1 prior metastatic therapy, and no prior platinum chemotherapy. By physician choice, patients received cisplatin 75 mg/m2 or carboplatin AUC 6 every 21 days (Figure 11). Co-primary endpoints were: 1) ORR and 2) p63/p73 expression by RT-PCR as a predictor of response. Tumor-based exploratory studies included: gene expression (GE) profiling, PIK3CA and p53 mutational status, and homologous recombination deficiency (HRD) assays correlating with BRCA1/2 inactivation.

Overall response rate by BRCA1/2 status was 54.5% (n /N = 6/11; 95% CI 23.4-83.3) for BRCA1/2 carriers compared to 19.7% (n = 13/66; 95% CI 10.9-31.3) for BRCA1/2 wild-type tumors (P = 0.02). In BRCA1/2 mutation and wild-type, PFS was 3.3 and 2.8 months (HR = 1.03 [0.53-2.00]; P = 0.92) and OS was 13.7 and 10.9 months (HR = 1.22 [0.53-2.00]; P = 0.58) (Table 7).

Among 61 patients evaluable, 28 (46%) had the pre-specified p63/p73 ratio ≥ 2, which did not predict response to platinum (ORR 18% vs 27% in p63/p73 ≥ 2 vs < 2, respectively, P = 0.54). 36/54

patients (67%) had p53 mutations, and 9/55 patients (16%) had PIK3CA mutations, but neither correlated with ORR. PAM50 analysis from global GE profiling identified 60% (32/53) basal-like tumors, which showed a higher ORR that did not reach significance (28% vs 10% in basal vs non-basal, P = 0.17). All HRD assays,

Figure 11. TBCRC009: study design and eligibility criteria.

Tumor EvaluationEvery 6 weeks (or 9) weeks

Progressionoff study

Cisplatin75 mg/m2

ORCarboplatin AUC 6

Every 3 (or 4) weeks until progression

Archived tumor block/slides and blood for correlative studies

REG

ISTE

R

Eligibility:• Triple negative by local assessment• Archived tissue from the primary or metastatic biopsy• RECIST 1.0 measurable disease• ECOG PS ≤ 2• No prior platinum treatment

Table 7. PFS and OS by BRCA status in triple-negative breast cancer.

BRCA Mutation BRCA Wild-Type

Median PFS, m 3.3 2.8

HR 1.03 (0.53-2.00)

P Value P = 0.92

Median OS, m 13.7 10.9

HR 1.22 (0.53-2.00)

P Value P = 0.58

HR, hazard ratio; OS, overall survival; PFS, progression-free survival.

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including Loss Of Heterozygosity (LOH), Telomere Allelic Imbalance (TAI), and Large-scale State Transition (LST), scored higher in BRCA1/2 carriers than non-carriers, and in responders than non-responders among the small group of 22 non-carriers with available tissue (HRD-LST responders vs non-responders, P = 0.0016).

Single-agent platinum is effective in both BRCA1/2-associated and sporadic metastatic triple-negative breast cancer. Although established biomarkers failed to predict responses, HRD assays may identify sporadic triple-negative breast cancer tumors that are BRCA1/2-like and responsive to platinum chemotherapy.

GeparSixto: Expression of Immunologic GenesIn the GeparSixto breast cancer trial, tumor-infiltrating lymphocytes (TILs) as predictors of pCR (pCR = ypT0ypN0) to neoadjuvant carboplatin-based chemotherapy were described. To further dissect the immunological status in tumor tissue, a total of 12 immunologically relevant genes, including T-cell markers, B-cell markers, chemokines, and immunoregulatory factors, in 481 pre-therapeutic FFPE samples were evaluated.

Dr Carsten Denkert presented data assessing the expression and prediction of response to immunologic genes in triple-negative breast cancer and HER2+ breast cancer in the neoadjuvant carboplatin-based GeparSixto trial.21 GeparSixto investigated the addition of carboplatin to a doxorubicin/taxane combination in HER2-positive (HER2+) or triple-negative primary breast cancer. Trastuzumab and lapatinib were added for HER2+ disease and bevacizumab for triple-negative disease. Expression of 12 immunologically relevant genes (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PDL1, CTLA4, FOXP3) was evaluated by quantitative RT-PCR in 481 core biopsies.

All immune mRNA markers showed a strong positive correlation with each other and with the stromal lymphocyte infiltrate. Hierarchical clustering revealed 3 different immune-subtypes of tumors with different expression of immunological genes and different amounts of tumor infiltrating lymphocytes: immune-type A (low expression of all immune genes), B (mixed group, which showed the expression of some markers), and C (nearly all immune genes were highly activated). Significantly higher rates of immune-C were detected in lymphocyte-predominant breast cancer cases (50%) compared with immune-B (19%) and immune-A (1%; P < 0.0001). There was also a significant correlation with pCR rates for immune-A (24%), immune-B (37%) and immune-C (56%; P < 0.00001) (Table 8).

Overall, in the GeparSixto cohort all 12 immune markers were significantly linked to increased pCR rates in univariate analysis and 11/12 were linked in the multivariate analyses. In triple-negative breast cancer (n = 255) 9/12 and in HER+ breast cancer 10/12 were significantly linked to greater pCR rates. Some markers, such as CCL5, IDO1, and PDL1 provided predictive information even if controlled for TILs. CCL5, CD8A, CTLA4, IDO1, and PD1 showed a significant interaction with treatment (carboplatin vs control) in the complete cohort. In triple-negative disease CCL5 and CD8A provided predictive information for carboplatin response even after adjustment for TILs.

Table 8. Immune type correlation with TIL morphology and pCR rates.

Immune-A Immune-B Immune-C

LPBC cases, % 1 19 50

P Value P < 0.00001

pCR rate, % 24 37 56

P Value P < 0.00001

LPBC, lymphocyte predominant breast cancer.



Expression of immune marker mRNAs in breast cancer is predictive for response to neoadjuvant chemotherapy. In GeparSixto, these immunological parameters can be used in addition to TILs to identify patients with increased response rates to carboplatin.

BRE-146: RNA-Sequencing of Triple-Negative Breast CancerDr Milan Rodavich presented biomarker data from the Hoosier Oncology Group Trial BRE-146 where RNA-sequencing of residual triple-negative breast cancers after neoadjuvant chemotherapy were compared to matched pre-treatment biopsies.22 Authors found that RNA-seq and histology identified significant depletion of immune cells in residual disease, which had been previously associated with poor prognosis in breast cancer. They further identified a highly activated MAPK1 network, suggesting the potential use of MEK/ERK inhibitors in clinical trials for this population. Lastly, authors identified a novel clinical biomarker, miR-663B, which is known to mediate in vitro triple-negative breast cancer resistance to doxorubicin, cyclophosphamide, and docetaxel.

CONCLUSION The 2014 ASCO Annual Meeting held in Chicago, Illinois provided an excellent forum to discuss recent treatment advances in clinical trial data and biomarker discoveries, ones that will assist clinicians in directing breast cancer treatment. The 2015 ASCO Annual Meeting will be held in Chicago, Illinois. Additional information can be obtained at www.asco.org.

REFERENCES1. Jamal A, Siegel R, Xu J, Ward E. Cancer Statistics, 2010. CA Cancer J Clin. 2010;60;277-300.2. Brewster AM, Hortobagyi GN, Broglio KR, et al. Residual risk of breast cancer recurrence 5 years after adjuvant therapy.

J Natl Cancer Inst. 2008;100:1179-1183.3. Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of breast cancer subtypes J Clin Oncol. 2010;28:3271-3277.4. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast

cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-1717.5. National Cancer Institute. SEER Stat fact sheets: breast. Available at: http://seer.cancer.gov/statfacts/html/breast.html. Accessed

June 10, 2014.6. American Cancer Society. Breast cancer facts & figures 2013-2014. Available at: http://www.cancer.org/acs/groups/content/@

research/documents/document/acspc-040951.pdf. Accessed June 10, 2014.7. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D)

comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T → L), or their combination (T + L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). J Clin Oncol. 2014;32:15(suppl). Abstract LBA4.

8. Carey LA, Barry WT, Pitcher B, et al. Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa). J Clin Oncol. 2014;32:15(suppl). Abstract 506.

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9. Carey LA, Berry DA, Ollila D, et al. Clinical and translational results of CALGB 40601: a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. J Clin Oncol. 2013;31(15 suppl). Abstract 500.

10. O’Sullivan CCM, Bradbury I, De Azambuja E, et al. Efficacy of adjuvant trastuzumab compared with no T for patients (pts) with HER2-positive breast cancer and tumors ≤ 2 cm: a meta-analysis of the randomized trastuzumab trials. J Clin Oncol. 2014;32:15(suppl). Abstract 508.

11. Pagani O, Regan MM, Walley B, et al. Randomized comparison of adjuvant aromatase inhibitor (AI) exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): Joint analysis of IBCSG TEXT and SOFT trials. J Clin Oncol. 2014;32:15(suppl). Abstract LBA1.

12. Gnant M, Mlinertisch H, Stoeger H, et al. Mature results from ABCSG-12: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer. J Clin Oncol. 2010;28(suppl). Abstract 533.

13. Moore HCF, Unger JM, Phillips KA, et al. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). J Clin Oncol. 2014;32:15(suppl). Abstract LBA505.

14. Tredan O, Follana P, Moullet I, et al. AROBASE: a phase III trial of exemestane (Exe) and bevacizumab (BEV) as maintenance therapy in patients (pts) with metastatic breast cancer (MBC) treated in first line with paclitaxel (P) and BEV—a Gineco study. J Clin Oncol. 2014;32:15(suppl). Abstract 501.

15. Miller K, O’Neill AM, Dang CT, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: final results from Eastern Cooperative Oncology Group E5103. J Clin Oncol. 2014;32:15(suppl). Abstract 500.

16. Earl HM, Hiller L, Blenkinsop C, et al. ARTemis: a randomised trial of bevacizumab with neoadjuvant chemotherapy (NACT) for patients with HER2-negative early breast cancer—primary endpoint, pathological complete response (pCR). J Clin Oncol. 2014;32:15(suppl). Abstract 1014.

17. Von Minckwitz G, Schneeweiss A, Salat C. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). J Clin Oncol. 2013;31(suppl). Abstract 1014.

18. V on Minckwitz G, Hahnen E, Fasching PA, et al. Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (gBRCA) mutation and triple-negative breast cancer (TNBC): results from GeparSixto. J Clin Oncol. 2014;32:15(suppl). Abstract 1005.

19. Paluch-Shimon S, Friedman E, Berger R, et al. Does pathologic complete response predict for outcome in BRCA mutation carriers with triple-negative breast cancer? J Clin Oncol. 2014;32:15(suppl). Abstract 1023.

20. Isakoff SJ, He L, Mayer EL, et al. Identification of biomarkers to predict response to single-agent platinum chemotherapy in metastatic triple-negative breast cancer (mTNBC): correlative studies from TBCRC009. J Clin Oncol. 2014;32:15(suppl). Abstract 1020.

21. Denkert C, Von Minckwitz G, Brase JC, et al. Expression of immunologic genes in triple-negative and HER2-positive breast cancer in the neoadjuvant GEPARSIXTO trial: prediction of response to carboplatin-based chemotherapy. J Clin Oncol. 2014;32:15(suppl). Abstract 510.

22. Radovich M, Hancock BA, Solzak JP, et al. RNA-sequencing of residual triple-negative breast cancers after neoadjuvant chemotherapy compared to matched pretreatment biopsies from the Hoosier Oncology Group trial BRE09-146. J Clin Oncol. 2014;32:15(suppl). Abstract 1002.

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