Clinical challenges in management of her 2 positive by gladwell kiarie

Images are not actual patients.

Dr. Gladwell G KiarieMedical Oncologist

Senior Lecturer University of Nairobi


Nairobi Cancer Registry, KEMRI

Cervix CancerNew cases: 4,802No. of Deaths: 2,451Age Standardized Incidence rates: 40.5/100,000

Breast CancerNew cases: 4,465No. of Deaths: 1,969Age Standardized Incidence rates 38.6/100,000

Kenya estimates (GLOBOCAN) 2012

OesophagusNew cases: 1,560Deaths: 1,428Age Standardized Incidence rates 15.1/100,000

Number of cases


Local Hormone Receptor Status

Her-2/neu positivity 20.26% 31%Her 2/new borderline 27.8%ER+ PR+ HER2+ 6.33% 11.9%ER- PR – HER 2 – 28% 17%ER- PR- HER 2 + 12.7% 10.2%ER+ PR + HER2 – 20.3% 12%

*(Anal Quant Cytol Histol, April 2006; 28 (2):97-103.* Unpublished data

In our study (66.9%) did the endocrine test while (65%) did the HER 2 test.


Case 168 yr old retired nurse known HTNThyroidectomy in 1990Nipple excoriation and some discharge, itching and

tingling.No palpable lump on breast or axillaMammogram: skin and areola thickening, nipple

retraction, subareolar and diffuse microcalcification. No discrete mass seen.


Histology report Case 1Core biopsy:StagingMastectomy and Axillary node sampling:

Pagets Disease DCIS grade 3 Invasive ductal carcinoma below the nipple Margins clear Lymph nodes negative (0/3) ER neg, PR neg and HER 2 pos (3 +)


Discussion PointsStaging : Bone Scan? PET CT ScanRadiation first?Adjuvant Chemotherapy (node negative)Herceptin : same period


APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Small, Node-negative HER2+ Breast CancerTolaney SM et al, SABCS 2013, abstract #S1-04

Randomized adjuvant HER2+ trials included few small, lymph node negative breast cancers

Patients: 406 pts with node-negative, HER2+ breast cancer, < 3 cm 2/3 ER+, 20% < 0.5 cm

Treatment: Paclitaxel and trastuzumab weekly x 12, followed by 9 months of single agent trastuzumab

Results: 3.6 years median follow-up 10 recurrences/deaths (2.5%): 2 distant, 4 locoregional, 3

contralateral breast cancers, 1 non-breast cancer death (ovarian ca)

3 year DFS 98.7%


APT Study: Phase II Study of Paclitaxel + Trastuzumab as Adjuvant Therapy for Small, Node-negative HER2+ Breast CancerTolaney SM et al, SABCS 2013, abstract #S1-04

Toxicity: 2 symptomatic CHF (resolved on stopping trastuzumab)13 asymptomatic declines in LVEF (able to resume

trastuzumab in 11)Conclusion: Paclitaxel plus trastuzumab can be considered

a reasonable approach for majority of patients with small, lymph node negative, HER2+ breast cancer


Case 2JO 36 yr old civil servant. Pregnant 16 weeks with a BOH. She is a sickler who

had lost a baby the previous year to sickle cell. Breast lump on the left breast with palpable axillary

nodes.Core biopsy: grade 3 IDC ER negative PR negative

HER 2 positive (3 +)Cardiac evaluation normal.


Management Case 2Staging Tests done Abd/ Pelvic ultrasoundSurgery : Lumpectomy was doneChemotherapyDelivered a bouncing baby boy weighing 3.2kgCompletion mastectomy?Radiation Tamoxifen and Herceptin


Trastuzumab in PregnancyThe majority of the women exposed to trastuzumab

developed oligo- or anhydraminos, and increases in amniotic fluid were observed when the drug is discontinued. ?directly causes a decrease in amniotic fluid, ?role of epidermal growth factor receptor (EGFR) in fetal

kidney development. Does Trastuzumab crosses the placenta?

direct evidence from humans is lacking, maternal-placental transfer of immunoglobulin-G1

antibodies such as rituximab occurs, studies in cynomologus monkeys show placental transfer of

trastuzumab during early and late gestation.


Trastuzumab in CNS Disease Brain Metastasis:

Trastuzumab (Herceptin), Lapatinib (Tykerb), Pertuzumab (Perjeta Ado-trastuzumab emtansine (Kadcyla) (T-DM1).

These drugs are not usually able to reach the brain as easily as they can reach the rest of the body, with lapatinib being a possible exception.

Therefore, when cancer spreads to the brain it is usually treated with surgery and/or radiation therapy.


Brain Metastasis in HER 2 positive Disease1. Surgery for single brain metastasis if the metastasis is > 3 to 4 cm or

if there is evidence of symptomatic mass effect. 2. Single brain metastasis < 3 to 4 cm without symptomatic mass effect

: stereotactic radiosurgery or surgical resection, depending on the location and surgical accessibility of the tumor, need for tissue diagnosis, and other considerations, such as medical risk factors for surgery and patient preference.

3. Surgical resection, with postoperative radiotherapy to the resection bed to reduce the risk of local recurrence.

4. Single brain metastasis > 3 to 4 cm that is deemed unresectable and unsuitable for stereotactic radiosurgery, clinicians may discuss the options of whole-brain radiotherapy or fractionated stereotactic radiotherapy.

5. After treatment, serial imaging every 2 to 4 months may be used to monitor for local and distant brain failure.


Cardiotoxicity with Herceptin Trastuzumab causes a form of cardiotoxicity not

dose-dependent, and ultrastructural changes typical of anthracycline therapy are not seen on cardiac biopsy specimens;

Cardiac dysfunction, is reversible in 60% of cases, and full LVEF recovery.

TNI measurement during trastuzumab therapy allows for identification of patients at risk of cardiotoxicity as well as of those who, despite HF therapy, will not recover from cardiac dysfunction.


Cardiotoxicity cont’dTroponin I (TNI) is an early marker of myocardial

injury, with high diagnostic and high prognostic TNI increase has been shown to predict LVEF

reduction and associated adverse cardiac events. The role of TNI in trastuzumab-treated patients has never been investigated.


Time of the first detection of elevated troponin value.

Cardinale D et al. JCO 2010;28:3910-3916

©2010 by American Society of Clinical Oncology


(A) Kaplan-Meier curve of time to first cardiac event in patients developing trastuzumab-induced cardiotoxicity (TIC) and in patients who did not (No TIC).

Cardinale D et al. JCO 2010;28:3910-3916

©2010 by American Society of Clinical Oncology


HER-2 Over-Expressing Breast Cancer

18

cell division

HER-2

nucleus

cancer cell

Trastuzumab Anti-HER-2 Antibody

HER-2 Oncogene: amplified and overexpressed in 20-25% HER-2 Oncogene: amplified and overexpressed in 20-25% of breast cancerof breast cancer

LapatinibDual HER-1/HER-2

Tyrosine Kinase Inhibitor

Pertuzumab Anti-HER-2

Antibody

T-DM1T-DM1Antibody-Drug

Conjugate


After Resistance to HER 2 inhibition


Metastatic Breast CancerPertuzumab + trastuzumab + taxaneEndochrine therapy + trastuzumab2nd line: Trastuzumab + TDMI3rd line: TDMI, pertuzumab, lapatinib and xeloda?resistance


The Concept of Trastuzumab Resistance

Definition of “trastuzumab resistance”No clear clinical definition

Described in terms of disease progression or recurrence on/after trastuzumab

Observed eventually in almost all HER2+ metastaticcancers1,2

Mechanisms contributing to such disease progressionStrategies to overcome these resistance mechanisms

1. Wong AL and Lee SC. Int J Breast Cancer. 2012;2012:415170. doi: 10.1155/2012/415170; 2. Arribas J, et al. Cancer Res. 2011;71(5):1515-1519.

Images are not actual patients.Reprinted from Romond EH, et al. NEJM. 2005;353(16):1673-1684. Copyright © 2005 Massachusetts Medical Society. All rights reserved.

HR = 0.47, P < .0001

0 1 2 3 4 5

50

60

70

80

90

100

ACPT 1672 96ACP 1679 193

N

ACPT

ACP

Trial B31/Trial N9831

Years From Randomization

90.4% 89.7%

81.5%

73.7%

? Trastuzumab-resistant

? No benefit from trastuzumab

Trastuzumabbenefit

Events


HER2

Alterations in downstream molecules: •Increased Akt signaling •PTEN deficiency •p27kip1 downregulation

Disrupted antibody-receptor interaction:•MUC-4

•HER2 mutations

Increased receptor signaling: •HER family members•Increased ligands•IGF-IR signaling/receptor crosstalk

Based on Bailey TA, et al. J Carcinog. 2011;10(1):28.


Emerging TherapiesReceptor level agents

Pertuzumab + trastuzumabLapatinib + trastuzumabHER2-specific tyrosine kinase inhibitors

Neratinib Afatinib

Downstream effectorsmTOR inhibitors

Everolimus


p85

G1

S

Translation(cyclin D1)

++

LAP

Emerging data support co-targeting the HER2 pathway in trastuzumab-resistant cancers

Based on Bailey TA, et al. J Carcinog. 2011;10(1):28.

NER/AFAT


Existing Strategies for Treatment of HER2+ Breast Cancer Progressing On/After TrastuzumabLapatinib1-3

Approved in combination with capecitabineContinuation of trastuzumab1-3

Retrospective and prospective studies demonstrate that continuing trastuzumab provides superiorclinical benefit1,2

T-DM13-5

Approved as monotherapy in 2013 based on EMILIA Additional recent data from TH3RESA6

1. Wong AL and Lee SC. Int J Breast Cancer. 2012;2012:415170. doi: 10.1155/2012/415170; 2. Gajria D and Chandarlapaty S. Expert Rev Anticancer Ther. 2011;11(2):263-275; 3. Jelovac D and Emens LA. Oncology (Williston Park). 2013;27(3):166-175. 4. Barginear MF, et al. Mol Med. 2013;18:1473-1479; 5. KADCYLA [package insert]. South San Francisco, CA: Genentech, Inc; 2013. Available at: http://www.gene.com/download/pdf/kadcyla_prescribing.pdf; 6. Wildiers H. ECCO-ESMO 2013. Abstract 15.

http://www.gene.com/download/pdf/kadcyla_prescribing.pdf


Median, months No. events

CAP + LAP 6.4 304

T-DM1 9.6 265Reprinted from Verma S, et al. NEJM. 2012;367(19):1783-1791. Copyright © 2012 Massachusetts Medical Society. All rights reserved. 27

CAP+ LAPNo. at risk by independent review:

0 2 4 6 8 10 12 14 16Time, mo

Pro

gres

sion

-fre

e su

rviv

al, %

18 20 22 24 26 28 30

496495T-DM1 404

419310341

176236

100

129183

73130

53101

3572

2554

1444

930

818

59

13

01

00

80

60

40

20 0

Stratified HR = 0.65 (95% CI, 0.55, 0.77) P < .001

PFS by Investigator Assessment

1:1

HER2+ (central) LABC or MBC (N = 991)

•Prior taxane and trastuzumab

•Progression on metastatic tx or within 6 mo of adjuvant tx

PDT-DM1T-DM1

3.6 mg/kg q3w IV3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w

+ Lapatinib

1250 mg/day orally qd

PD


TH3RESA: T-DM1 Improved PFS Versus Physician’s Treatment of Choice for HER2+ mBC

N ~ 600•Locally advanced or metastatic HER2+ breast cancer •Prior Trastuzumab, taxane, and lapatinib•Disease progression after ≥2 regimens HER2-directed therapy in metastatic/ recurrent setting

T-DM1 (3.6 mg/kg) T-DM1 (3.6 mg/kg) every 21 daysevery 21 days

Treatment of physician’s choice

• Treatment continued until disease progression or intolerable toxicity• Estimated completion date: June 2015

R2:1

Key endpoints:• Primary: PFS by

investigator assessment per RECIST, OS

• Secondary: ORR

Median follow-up: Treatment of Physician’s Choice (TPC), 6.5 months; T-DM1, 7.2 months. Unstratified HR = 0 (P < 0.0001).Wildiers H. ECCO-ESMO 2013. Abstract #15.

UNPUBLISHED DATA REMOVED


Trastuzumab: 4 mg/kg load Trastuzumab: 4 mg/kg load 2 mg/kg qw 2 mg/kg qw oror 8 mg/kg load 8 mg/kg load 6 mg/kg q3w 6 mg/kg q3wPertuzumab: 840 mg load Pertuzumab: 840 mg load 420 mg q3w 420 mg q3w

N = 66• HER2+

(HercepTest)1,2

• Progressed on trastuzumab-based therapy as most recent treatment

Primary endpoint:Overall response rate and/or CBR

Secondary endpoints include:•Safety•Duration of response•Time to response•TTP•PFS

Response Patients (N = 66)

CR 7.6%

PR 16.7%

SD ≥ 6 mo 25.8%

ORR 24.2%

CBR 50%

Median PFS: 5.5 mo

1. Baselga J, et al. JCO. 2010;28(7):1138-1144; 2. Birner P, et al. CCR. 2001;7(6):1669-1675.


Lapatinib (1500 mg/day PO)(n = 148)

Lapatinib (1000 mg/day PO) + Trastuzumab

(4 mg/kg load 2 mg/kg weekly)(n = 148)

N = 296• HER2+ (FISH+/IHC 3+)• Progressed on most recent

trastuzumab regimen• Prior anthracycline- and

taxane-based regimens

Primary endpoint:Progression-free survival: Investigator

Secondary endpoints include:•Overall survival•Overall response rate•Clinical benefit rate•Quality of life •Safety

Crossover if PD after 4 wk therapy (N = 73)

RANDOMIZE

Schematic based on data from Blackwell KL, et al. JCO. 2010;28(7):1124-1130. Figure reprinted from Blackwell KL, et al. JCO. 2012;30(21):2585-2592. Copyright © 2012 American Society of Clinical Oncology. All rights reserved.

L + TL

No. at risk

L + TL

Ove

rall

Su

rviv

al, %

Time Since Random Assignment, months

100

80

60

40

20

105 15 20 25 30 35

80%

70%56%

41%

6-month OS

12-month OS

L + T(n = 146)

L(n = 145)

Died, n (%)Median, monthsHR (95% CI)Log-rank P .026

00

87120 63 42 25 114664100 46 28 13145

0.74 (0.57 to 0.97)

113 (78) 105 (72)9.5 14


Neratinib (240 mg/day PO)Neratinib (240 mg/day PO)Prior trastuzumab treatmentPrior trastuzumab treatment

(n = 66)(n = 66)

Neratinib (240 mg/day PO) Neratinib (240 mg/day PO) No prior trastuzumab treatmentNo prior trastuzumab treatment

(n = 70)(n = 70)

N = 136• HER2+ (FISH+)• Prior cytotoxic and

trastuzumab-based regimens

a Confirmed response.b Exact CIs were constructed.c CR + PR + stable disease ≥ 24 weeks. Burstein HJ, et al. JCO. 2010;28(8):1301-1307.

RANDOMIZE

Clinical Activity Prior T N = 63

No Prior T N = 64

16-wk PFS rate (95% CI) 59% (45 to 71) 78% (66 to 87)

Median PFS, wk (95% CI) 22.3 (15.9 to 31.6) 39.6 (31.0 to 55.1)

Objective response rate, %a (95% CI)b 24 (14-36) 56 (43-69)

Stable disease time, %<24 weeks≥24 weeks

3310

2013

Clinical benefit rate, %c (95% CI)b 33 (22-46) 69 (56-80)


N = 45 •HER2+ ABC

•Progression on prior trastuzumab

Neratinib (240 mg/day)+ TRAS (2 mg/kg/wk)

Neratinib (160 mg/day)+ TRAS (2 mg/kg/wk)a

n = 4

Neratinib (240 mg/day)+ TRAS (2 mg/kg/wk)a

n = 4

Phase 1: Dose Escalation (N = 8)Phase 2 (N = 37)

Clinical Activity N = 33b

Objective response rate, % (95% CI) 27 (13-46)16-week progression-free survival rate, % (95% CI) 47 (29-63)Median PFS, weeks (95% CI) 19 (15-32)

a Following a loading dose of 4 mg/kg.b Evaluable for efficacy (phase 2).Swaby R, et al. ASCO 2009, Abst 1004 (abstract).

OR

No dose-limiting toxicities observed


Phase 2 Trial: Afatinib Monotherapy in Heavily Pretreated HER2+ MBC Progressing After Trastuzumab

N = 41 •HER2+ (IHC2+/FISH+)•Progression on prior trastuzumab or trastuzumab-based chemotherapy

Afatinib (50 mg/day)

Lin NU, et al. BCRT. 2012;133:1057-1065.

Best Response(RECIST)

All treated Patients, %

(N = 41)

Evaluable Patients, %a

(N = 35)

Median duration, weeks (range)

CBR (CR + PR + SD) 46 54 17.1 (7.3-64.0)

PR 10 11 12.0 (7.4-56.1)

Stable disease 37 43 –

Progressive disease 39 46 –

Median PFS: 15.1 weeksMedian OS: 61.0 weeks


Phase 3 Trial: Trastuzumab + Vinorelbine ± Everolimus in Heavily Pretreated MBC Following Progression on Trastuzumab (BOLERO-3)

a Actual enrollment was 569.b Following a 4-mg/kg loading dose on day 1, cycle 1 (1 cycle = every 21 days). O’Regan RM, et al. ASCO 2013, Abst 505 (oral presentation).

N = 572a

•Locally advanced or metastatic HER2+ breast cancer •Prior taxane required•TRAS resistance–Adjuvant: progression on or within 12 months of TRAS –Metastatic: progression within 4 weeks of TRAS

•Measurable disease only

Everolimus (5 mg PO daily) + Vinorelbine (25 mg/m2 weekly)

+ TRAS (2 mg/kg weeklyb)(n = 284)

Therapy until progressive disease or intolerable toxicity

Placebo (PO daily) + Vinorelbine (25 mg/m2

weekly) + TRAS (2 mg/kg weeklyb)(n = 285)

RANDOMIZE1:1

• Stratification by prior lapatinib use (yes/no)

Primary endpoint:Progression-free survival

Secondary endpoints include:•Overall survival•Overall response rate•Time to deterioration of ECOG PS•Safety•Duration of response•Clinical benefit rate•Quality of life


HER2-Positive Breast Cancers Are Intrinsically Resistant to Endocrine Therapy

Transfection of ER+ breast cancer cells with HER2 renders them resistant to tamoxifen1

Retrospective analyses of trials in the ER+ metastatic setting show a worse outcome for cancers that co-express HER2 compared to those that do not2

Median progression-free survival is less than 6 months for ER+, HER2+ MBC treated with aromatase inhibitors3,4

1. Benz CC, et al. BCRT. 1992;24(2):85-95; 2. De Laurentiis M, et al. CCR. 2005;11(13):4741-4748; 3. Kaufman B, et al. JCO. 2009;27(33):5529-5537; 4. Johnston S, et al. JCO. 2009;27(33):5538-5546.


HER2– HER2+/–

Reprinted from Nahta R and O’Regan R. BCRT. 2012;135(1):39-48.


But is this true for all ER+, HER2+ breast cancers?

HER2

ER


T TTTT LLLL T/LT/LT/LT/L P T/P T/P

PTX PTXFEC FECPTX DECD

Per

cen

t PC

R

Nahta R and O’Regan R. BCRT. 2012;135(1):39-48.


Hazard ratio = 5.24 (95% CI, 2.25-12.1)P < .001 log-rank test

Hazard ratio = 0.88 (95% CI, 0.38-2.06)P = .775 log-rank test

ER-negative, HER2-positiveDFS

ER-positive, HER2-positive DFS

Reprinted from von Minckwitz G, et al. SABCS 2011, Abst S3-2 [presentation].

UNPUBLISHED DATA REMOVED


Why Is This Important?We may be (and probably are) over-treating a subgroup

of ER+, HER2+ breast cancers in the (neo)adjuvant settingThis subgroup of patients with ER+, HER2+ breast cancers

may suffer late recurrences (similar to what we see with luminal A cancers)


HER2+/ER–

HER2+/ER+

HER2+/ER+++

Per

cen

t PC

R

ER expression

1. Bhargava R, et al. Mod Pathol. 2011;24(3):367-374; 2. Reprinted from Nahta R and O’Regan R. BCRT. 2012;135(1):39-48.

Images are not actual patients.Reprinted from Knauer M, et al. British J Cancer. 2010;103(12):1788-1793.

Distant Disease-Free Survival

Good prognosisPoor prognosis

Per

cen

t su

rviv

al

Log-rank (Mantel–Cox) test Log-rank (Mantel–Cox) testP value 0.0170 0.0523

100

80

60

40

20

0

Per

cen

t su

rviv

al

100

80

60

40

20

0

Time, years0

Time, years

Good prognosisPoor prognosis

P value

2 4 6 8 10 0 2 4 6 8 10

Breast Cancer-Specific Survival


Bi-Directional Crosstalk Between ER and HER2Signaling through EGFR family including HER2

downregulates ER1,2

Conversely, inhibition of HER with trastuzumab or lapatinib increases signaling through ER3,4

ER signaling is increased in HER2-positive cell lines that are resistant to HER2-directed agents4,5

HER2 expression and activity are increased in hormone-resistant cancers, compared with hormone-sensitive cancers6,7

1. Pinzone JJ, et al. Mol Cell Biol. 2004;24(11):4605-4612; 2. Stoica A, et al. J Endocrinol. 2000;165(2):371-378;3. Sabnis G, et al. Cancer Res. 2009;69(4):1416-1428; 4. Xia W, et al, Proc Natl Acad Sci. 2006;103(20):7795-7800; 5. Valabrega G, et al. Oncogene. 2005;24(18):3002-3010; 6. Gee JM, et al. Endocr Relat Cancer. 2005;12(Suppl 1):S99-S111; 7. Johnston SR. CCR. 2005;11(2 Pt 2):889s-889s.


ERER

ERE

FOXO3a

PI3-K

AKT

HER2 HER1/2/3

FOXO3a

ER-regulated genetranscription

x

Ras

MEK

Erk1/2

Nucleus

Cytoplasm

Membrane

ERER

ERE

FOXO3a

PI3-K

AKT

HER2 HER1/2/3

ER-regulatedgene transcription

Ras

MEK

Erk1/2

Nucleus

Cytoplasm

Membrane

TKITKIxx

TRASTTRAST

1. Xia W, et al. Proc Natl Acad Sci. 2006;103(20):7795-7800; 2. Valabrega G, et al. Oncogene. 2005;24(18):3002-3010; 3. Reprinted from Nahta R and O’Regan R. BCRT. 2012;135(1):39-48.


Clinical Relevance of This Crosstalk Inhibition of HER2 without inhibition of ER may

increase ER signaling, allowing ER to act as an escape mechanism This could contribute to the lower PCR seen in ER+, HER2+

breast cancers in the neoadjuvant setting, and this could have potential implications in the metastatic setting Potential reason for smaller PFS benefit observed in ER+, HER2+

versus ER–, HER2+ subsets in BOLERO-3? There may be a subset of ER+, HER2+ breast cancers where

ER inhibition is critical A few patients demonstrated a change from ER– to ER+

following trastuzumab-based chemotherapyMittendorf EA, et al. CCR. 2009;15(23):7381-7388.


Role of ER in Trastuzumab Resistance

Although HER2 signaling is associated with intrinsic resistance to endocrine agents, a subset of HER2+, ER+ cancers appears to be driven, at least in part, by ER

Identification of these cancers is crucial They may require less aggressive treatment

approaches with earlier institution of ER inhibition They may behave like ER+, HER2– cancers with late

relapses ER plays a role in resistance to HER2-directed

agents


HER2 Therapy CombinationsHER2 Therapy Combinations

Neo ALTTO: Preop HER2+Neo ALTTO: Preop HER2+Baselga J et al, Lancet 379:633-640, 2012Baselga J et al, Lancet 379:633-640, 2012

Invasive, operableHER2+ breast

cancerT > 2 cm

N=450

lapatiniblapatinib

trastuzumabtrastuzumab

lapatiniblapatinibtrastuzumabtrastuzumab

FEC

X

3

SURGERY

RANDOMIZE

Lapatinib 1500 mg/d Lapatinib 1500 mg/d

Trastuzumab weeklyTrastuzumab weekly

Lapatinib 1000 to 750Lapatinib 1000 to 750trastuzumabtrastuzumab

paclitaxel paclitaxel 80 mg/m2 80 mg/m2

paclitaxel paclitaxel

paclitaxelpaclitaxel

pCR


Neo ALTTO: Survival Follow-up AnalysisPiccart M et al, SABCS 2013 abstract #S1-01

Lapatanib + Lapatanib + TrastuzumabTrastuzumab

TrastuzumabTrastuzumab LapatinibLapatinib

3 yr EFS (all) 84% 78% 78%

HR+ 83% 80% 86%

HR- 86% 72% 70%

3 yr OS (all) 95% 90% 93%

HR+ 97% 94% 93%

HR- 93% 87% 93%

None statistically significantNone statistically significant


Neo ALTTO Survival Follow-up Analysis: Conclusions Underpowered to detect moderate EFS and OS

differences, await results of ALTTO adjuvant trial Patients who achieved pCR had significantly better EFS Patients who achieved pCR had significantly better EFS

and OS compared with no pCRand OS compared with no pCR• HER2+/ER- disease different from HER2/ER+ disease


Conclusion“In the management of patients with breast cancer,

selecting the most efficacious therapy remains a challenging but achievable goal. Improved understanding of the targets for therapy has made possible an unprecedented level of insight into the individual patient’s cancer genome and biology. Concurrent development of predictive biomarkers along with targeted therapies is the new paradigm for achieving optimal care and sparing patients unnecessary toxicity and expense”.

Investor Relations

Clinical challenges in management of her 2 positive by gladwell kiarie