chemotherapy with or without targeted drugs* in … · with primary and metastatic breast cancer...

Diagnosis and Treatment of Patients

with Primary and Metastatic Breast Cancer

© AGO e. V. in der DGGG e.V.

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Guidelines Breast

Version 2015.1

Chemotherapy With or Without

Targeted Drugs* in Metastatic

Breast Cancer

*Substances are only discussed if there is at least published evidence

based on one phase III / IIb study available


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Chemotherapy Targeted Drugs in

Metastatic Breast Cancer

Version 2002:

von Minckwitz / Schaller / Untch

Versions 2003–2014:

Bischoff / Dall / Fersis / Friedrichs / Harbeck /

Jackisch / Janni / Möbus / Rody / Scharl /

Schmutzler / Schneeweiss / Schütz / Stickeler

/Thomssen

Version 2015:

von Minckwitz / Müller


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Disease-Free and Overall Survival

in Metastatic Breast Cancer

An increase in survival over time in MBC has 2a

been shown in some retrospective analyses

However, patients with MBC today have received 2a

more adjuvant treatment and have therefore

considered more drug resistant

Multiple lines of sequential therapy are 1b

beneficial (at least same efficacy, less toxicity)

Especially targeted drugs in combination with 1b

chemotherapy can induce substantial survival

benefits

Oxford / AGO

LoE / GR


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Guidelines Breast

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Treatment of Metastatic Breast Cancer

Predictive Factors

Therapy Factor

Endocrine therapy ER / PR

(primary tumor, metastasis) 1a A ++

previous response 2b B ++

Chemotherapy previous response 1b A ++

Anti-HER2-drugs HER2

(primary tumor,

better metastasis) 1a A ++

Bone modifying drugs bone metastasis 1a A ++

Any therapy CTC monitoring 1b A +*

(other potentially biological factors see chapter „Predictive factors“)

Oxford / AGO

LoE / GR

*within clinical trials


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Cytotoxic Therapy

Goals

Mono-Chemotherapy: Favourable therapeutic index

Indicated in case of

Slow, not life-threatening progression

Insensitive to or progression during endocrine therapy

Poly-Chemotherapy: Unfavourable therapeutic index

Indicated to achieve rapid remission in the case of

Extensive symptoms

Imminent life-threatening metastases

Survival benefit in comparison to sequential single-agent therapies with the same compounds not proven

Oxford LoE: 1b GR: A AGO: ++

Therapeutic index evaluates overall efficacy, toxicity and impact on quality of life


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Cytotoxic and Targeted Therapy

Evaluate compliance before and during therapy (especially

in patients of older age, with reduced performance status,

or significant co-morbidities)

Assess subjective and objective toxicities, symptoms, and

performance status repeatedly

Use dosages according to published protocols

Assess tumor burden at baseline and approx. every 2

months, i.e. every 2-4 cycles. Assessment of a target

lesion might be sufficient. In slowly growing disease,

longer intervals are acceptable.

LoE: 1c GR: A AGO: ++


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Cytotoxic Therapy

Duration

Oxford / AGO

LoE GR

As long as therapeutic index remains positive 1a A ++

Treatment until progression 2b B +

Treatment until best response 2b B +/-

Change to alternative regimen

before progression 2b B +/-

Stop therapy in case of 1c A ++

Progression

Non tolerable toxicity


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Chemotherapy for MBC – General

Considerations: Drug Selection

The choice of cytotoxic drugs to be used depends on:

ER / PR, HER2; combination with biologicals

Previous treatments (and their toxicities)

Disease-free interval after end of adjuvant treatment

Aggressiveness of disease and localization of metastases

Estimated life expectancy

Co-morbidities (including organ dysfunctions)

Patients preference and expectations

AGO: ++


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MBC HER2-negative/HR-positive

Cytotoxic 1st-Line Therapy*

Monotherapy: Paclitaxel (q1w), Docetaxel (q3w) 1b A ++ Doxorubicin, epirubicin, mitoxantrone (A)

Peg. liposomal doxorubicin (Alip) 1b A ++ Vinorelbine 3b B + Capecitabine 2b B + Nab-paclitaxel 2b B +

Polychemotherapy:

A + T 1b A ++ T + gemcitabine after adj. A 2b B ++ A + C or Alip + C 1b B ++ Paclitaxel + capecitabine 2ba B + Docetaxel + capecitabine after adj. A 1b A +

Oxford / AGO

LoE / GR

*In ER pos. disease only if endocrine therapy is not or not anymore indicated


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MBC HER2-negative/HR-pos: Cytotoxic

Therapy after Anthracycline Treatment*

Paclitaxel q1w 1a A ++

Docetaxel q3w 1a A ++

Capecitabine 2b B ++

Nab-paclitaxel 2b B ++

Peg-liposomal doxorubicin 2b B +

Eribulin 1b B +

Vinorelbine 2b B +

Docetaxel + Peg-liposomal Doxo 1b B +/-

Oxford / AGO

LoE / GR

*independent whether anthracyclines were used in adjuvant

or 1st line metastatic situation


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MBC HER2-negative/HR-positive: Cytotoxic

Therapy after adjuvant Taxane and

Anthracycline Treatment

Experimental therapies within studies ++

Capecitabine 2b B ++

Eribulin 1b B ++

Vinorelbine 2b B ++

(Peg)-liposomal Doxorubicin 2b B +

Gemcitabine + Cisplatin / Carboplatin 2b B +/-

Gemcitabine + Capecitabine 2b B +/-

Gemcitabine + Vinorelbine* 1b B -

*Cave neutropenia / therapeutic index!

Oxford / AGO

LoE / GR


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Triple Negative Metastatic Breast

Cancer

Experimental therapies within studies ++

Cytotoxic therapy as for patients with

HR pos / HER2 neg. mBC +

Carboplatin (vs. Docetaxel) 1ba B +/-

in gBRCA mutation 1ba B +

Gemcitabine/Cisplatin (vs. GemPac) 1ba A +

Bevacizumab added to first line cytotoxic

therapy 2b B +

Oxford / AGO

LoE / GR


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1st line in combination with:

Paclitaxel (q1w) 1b B +

Capecitabine 1b B +

Anthracyclines 2b B +/-

Nab-Pac 2b B +/-

Docetaxel (q3w) 1b B +/-

Cap+Bev as maintenance after Doc+Bev 1b B +/-

2nd line as treatment through multiple lines 1b B +/-

2nd line in combination with:

Taxanes 1b B +/-

Capecitabine 1b B +/-

Gemcitabine or vinorelbine 1b B -

Oxford / AGO

LoE / GR

Bevacizumab Treatment in

HER2-neg. Metastatic Breast Cancer


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First Line Therapy of HER2 Overexpressing


Docetaxel + trastuzumab + pertuzumab 1b A ++

(nab)Paclitaxel + trastuzumab + pertuzumab 2b B +

T-DM 1 (relapse within 6 months after taxane and

trastuzumab-pretreatment) 2b B +

1st line chemotherapy* + trastuzumab 1b B +

Trastuzumab mono 2b B +/-

Taxanes + lapatinib 1ba B -

Taxanes + trastuzumab + everolimus 1ba B -

Trastuzumab + aromatase inhibitors (if ER+) 2b B +/-**

Lapatinib + aromatase inhibitors (if ER+) 2b B +/-** *Taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel

**see chapter Endocrine +/- targeted

Oxford / AGO

LoE / GR


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2nd line Therapy of HER2-positive mBC (If Pretreatment with Trastuzumab)

T-DM 1 1b A ++

TBP: 2nd line chemotherapy + trastuzumab 2b D +

Capecitabine + lapatinib 1b B +

Trastuzumab + lapatinib (HR neg. disease) 2b B +

Taxane + trastuzumab + pertuzumab 5 D +

Any other 2nd line chemotherapy* +

trastuzumab + pertuzumab 5 D +/-

Trastuzumab + aromatase inhibitors (if ER+) 3b B +

Lapatinib + aromatase inhibitors (if ER+) 3b B +

*e.g. vinorelbine; taxane/carboplatin; capecitabine/docetaxel (toxicity!)

Oxford / AGO

LoE / GR


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Further Lines of Therapy of HER2-Positive


Pretreatment with Trastuzumab

T-DM 1 1b A ++

Capecitabine + lapatinib 1b B +

Trastuzumab + lapatinib (HR neg. disease) 2b B +

Chemotherapy + trastuzumab + („treatment

beyond progression“) 2b B +

Trastuzumab + pertuzumab 2b B +

Vinorelbine + trastuzumab + everolimus 1b B +/-

There is no data for patients pretreated with trastuzumab and pertuzumab

Experimental anti-HER2-regimen 5 D +

For patients pretreated with trastuzumab and pertuzumab 5 D treatment according to the recommendations above.

There is no data for treatment beyond progression for pertuzumab.

Oxford / AGO

LoE / GR


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In combination with

Trastuzumab for heavily

pre-treated pts 2b B +

Paclitaxel in 1st line 2b B -

Capecitabine in > 2nd line 1b B +

AI in ER positive disease 2b B +/-

In patients with brain metastases

(radioresistance) in combination

with capecitabine 2b B +/-

Oxford / AGO

LoE / GR

Lapatinib in HER2-positive


© AGO e.V. in der DGGG e.V.

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Guidelines Breast

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© AGO e.V. in der DGGG e.V.

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Guidelines Breast

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Immunodiagnostic Tests

and Immunotherapy

Immunodiagnostic tests: Immunological parameters in peripheral blood 5 D --

Local immunotherapy

Imiquimod topically for skin metastases 4 C +/- Systemic immunotherapy - including items below – only within clinical trials: ++ HER2-vaccination in high risk population Immunomodulation (e.g. addition of Nov-2 to AC –T) Dendritic cell intradermal vaccination Active vaccination Passive vaccination Therapy with oncolytic viruses Cytokines Checkpoint inhibitors (PD1; PDL-1;…)

Oxford / AGO

LoE / GR

Chemotherapy With or Without Targeted Drugs in Metastatic Breast Cancer (2/18)

Further information and references:

International consensus

Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL, Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, Gelmon K, Giordano SH, Gligorov J, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver SD, Nordstrom EB, Pagani O, Partridge A, Penault-Llorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C, Van't Veer L, Vorobiof D, Vrieling C, West N, Xu B, Winer E. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol. 2014;25:1871-88.

Update since 2013 based on versions 2012.1 E (fusion of Chapter 21, Cytotoxic Therapy in Metastatic Breast Cancer, and

Chapter 25, Targeted Agents).

Disease-Free and Overall Survival in Metastastic Breast Cancer (3/18)

No further information

References:

Increase

1. Petrelli F, Barni S. Surrogate endpoints in metastatic breast cancer treated with targeted therapies: an analysis of the

first-line phase III trials. Med Oncol. 2014;31:776.

More adjuvant..

Multiple lines

1. Qi WX, Tang LN, He AN, Shen Z, Yao Y. Comparison between doublet agents versus single agent in metastatic

breast cancer patients previously treated with an anthracycline and a taxane: a meta-analysis of four phase III trials.

Breast. 2013;22:314-9.

Treatment of Metastatic Breast Cancer - Predictive Factors (4/18)


References:

CTC monitoring

1. Bidard FC, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA,

Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, De Mattos-Arruda L, Ignatiadis M,

Lebofsky R, van Laere SJ, Meier-Stiegen F, Sandri MT, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-

Rubio E, Krell J, Dawson SJ, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix

L, Solomayer EF, Zorzino L, Johannes H, Reis-Filho JS, Pantel K, Pierga JY, Michiels S. Clinical validity of

circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet

Oncol. 2014;15:406-14.

(Hilner et al. 2003 JCO)

Cytotoxic Therapy Goals (5/18)


(O’Shaugnessy et al, 2003, Albain, 2004)

(Sledge et al, 2003).

(S Carrick et al, The Cochrane Database of Systematic Reviews 2005)

2013

Combination vs single agent

1. Qi WX, Tang LN, He AN, Shen Z, Yao Y. Comparison between doublet agents versus single agent in metastatic

breast cancer patients previously treated with an anthracycline and a taxane: A meta-analysis of four phase III trials.

Breast. 2012 Aug 14. [Epub ahead of print] – no OS advantage

2. Belfiglio M, Fanizza C, Tinari N, Ficorella C, Iacobelli S, Natoli C; Consorzio Interuniversitario Nazionale per la

Bio-Oncologia (CINBO). Meta-analysis of phase III trials of docetaxel alone or in combination with chemotherapy

in metastatic breast cancer. J Cancer Res Clin Oncol. 2012 Feb;138(2):221-9. doi: 10.1007/s00432-011-1091-0.

Epub 2011 Nov 18. - no OS advantage

Docetaxel alone or in combination

Metaanalysis; MBC

Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and

ORR in MBC.



in metastatic breast cancer. J Cancer Res Clin Oncol. 2012 Feb;138(2):221-9.

Single trials:

Combination not superior compared to single agent regimen.

1. Pallis AG, Boukovinas I, Ardavanis A, Varthalitis I, Malamos N, Georgoulias V, Mavroudis D. A multicenter

randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and

taxane-pretreated women with metastatic breast cancer. Ann Oncol. 2012 May;23(5):1164-9.

Tailored therapy in MBC

Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with

limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into

clinically relevant improvement of the outcome.

1. Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S,

Söderberg M, Sundquist M, Walz TM, Hellström M, Svensson H, Aström G, Brandberg Y, Carstensen J, Fernö M,

Bergh J. Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line

chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012

Feb;131(3):939-47.

Cytotoxic and Targeted Therapy (6/18)


References:

1. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, Barrios CH, Bergh J, Biganzoli L, Blackwell KL,

Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, Gelmon K, Giordano SH, Gligorov J,

Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver

SD, Nordstrom EB, Pagani O, Partridge A, Penault-Llorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C, Van't Veer

L, Vorobiof D, Vrieling C, West N, Xu B, Winer E. ESO-ESMO 2nd international consensus guidelines for advanced

breast cancer (ABC2)dagger. Ann Oncol. 2014;25:1871-88.

Cytotoxic Therapy Duration (7/18)

Further information:

Consent

Treatment until progression 6++, 18+, 2+/-,1-

Treatment until best response 1++, 3+, 23+/-,1-

Change to alternative regimen before progression 1++, 0+, 25+/-, 5-

References:

Change to alternative regimen before progression:

1. Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung

U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line

bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised,

open-label, phase 3 trial. Lancet Oncol. 2014;15:1351-60.

Treatment until progression

1. Gennari A, Stockler M, Puntoni M, Sormani M, Nanni O, Amadori D, Wilcken N, D'Amico M, DeCensi A, Bruzzi

P. Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of randomized

clinical trials. J Clin Oncol. 2011;29:2144-9.

2. Alba et al. Breast Cancer Res Treat 2010

3. Park et al. JCO 2013

Chemotherapy for MBC – General Considerations: Drug Selection (8/18)

Further information:

The selection of the drugs and drug combinations should take into account patients expectations, general health conditions,

aggressiveness of the disease, localisation of metastases and previous therapies.

References:

2013

Quailty of life: Paclitaxel/gemcitabie vs paclitaxel-mono. Combination tends to be better

1. Moinpour CM, Donaldson GW, Liepa AM, Melemed AS, O'Shaughnessy J, Albain KS. Evaluating health-related

quality-of-life therapeutic effectiveness in a clinical trial with extensive nonignorable missing data and

heterogeneous response: results from a phase III randomized trial of gemcitabine plus paclitaxel versus paclitaxel

monotherapy in patients with metastatic breast cancer. Qual Life Res. 2012 Jun;21(5):765-75.

Limitations of palliative chemotherapy

1. Ribeiro JT, Macedo LT, Curigliano G, Fumagalli L, Locatelli M, Dalton M, Quintela A, Carvalheira JB, Manunta S,

Mazzarella L, Brollo J, Goldhirsch A. Cytotoxic drugs for patients with breast cancer in the era of targeted treatment:

back to the future? Ann Oncol. 2012 Mar;23(3):547-55.

Metaanalyses

HRQOL is one of the key indicators of treatment benefit in advanced breast cancer, but contemporary systemic therapies

in this setting do not appear to affect HRQOL differentially.

1. Adamowicz K, Jassem J, Katz A, Saad ED. Assessment of quality of life in advanced breast cancer. An overview of

randomized phase III trials. Cancer Treat Rev. 2012 Aug;38(5):554-8.

MBC HER2 negative Cytotoxic 1st-Line Therapy (9/18)


1. O'Shaughnessy JA, Kaufmann M, Siedentopf F, Dalivoust P, Debled M, Robert NJ, Harbeck N. Capecitabine monotherapy: review of studies in first-line HER-2-negative metastatic breast cancer. Oncologist. 2012;17:476-84.

Liposomal doxorubicin is equally effective to doxorubicin but has less cardio and myelotoxicity but more skin toxicity

(O’Brien et al, 2004).

Polychemotherapy with anthracyclines and taxanes induce high remission rates but are more toxic then anthracycline or

taxane free combinations.

After anthracycline treatment two studies could show a survival benefit with gemcitabine paclitaxel or with

Docetaxel/Capecitabine (O’Shaugnessy et al, 2002 and Albain, 2004).

Retrospective date show that patients who respond to first line therapy with a complete response have a survival benefit

compared to patients without CR (Greenberg et al, 1996).

Doxorubicin/docetaxel vs. Doxorubincin/paclitaxel as first line treatment in metastatic breast cancer (ERASME3-study)

did not show any significant differences in terms of efficacy and overall QoL. Cassier et al., Breast Cancer Research and

Treatment (electronic publication 2007).

2013

Individual trials

1. Taxanes +/- Bevacizumab

2. NabPaclitaxel vs Ixabepilone vs paclitaxel

1. Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Mayer EL, Naughton M, Layman RM, Carey LA,

Somer RA, Perez EA, Hudis C, Winer EP (2012) CALGB 40502/NCCTG N063H: Randomized phase III trial of

weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with

or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin

Oncol 30, 2012 (suppl; abstr CRA1002)

Nab-Paclitaxel

1st line MBC, rand Phase II (n=302

Treatment with nab-paclitaxel 150 mg/m(2) qw 3/4 resulted in a median overall survival (OS) of 33.8 months compared

with 22.2, 27.7, and 26.6 months for nab-paclitaxel 100 mg/m(2) qw 3/4, nab-paclitaxel 300 mg/m(2) q3w, and docetaxel,

respectively (overall P = .047).

A trend toward a longer OS was noted in the 150 mg/m(2)nab-paclitaxel arm versus docetaxel arm (hazard ratio, 0.688).

Grade 3 or 4 fatigue, neutropenia, and febrile neutropenia were less frequent in all nab-paclitaxel arms compared with

docetaxel.

1. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P, McGuire JR, Iglesias J.

Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast

cancer: final analysis of overall survival. Clin Breast Cancer. 2012 Oct;12(5):313-21.

Ixabepilone + capecitabine vs capecitabine alone in 1st line MBC

1. Jassem J, Fein L, Karwal M, Campone M, Peck R, Poulart V, Vahdat L. Ixabepilone plus capecitabine in advanced

breast cancer patients with early relapse after adjuvant anthracyclines and taxanes: a pooled subset analysis of two

phase III studies. Breast. 2012 Feb;21(1):89-94.

Results: In 293 patients, ixabepilone plus capecitabine, as compared to capecitabine alone, increased PFS (median: 5.6

months vs. 2.8 months; hazard ratio, 0.58; p < 0.0001), ORR (46% vs. 24%) and OS (median: 15.1 months vs. 12.5

months; hazard ratio, 0.84; p = 0.208). Major toxicities of this regimen included neuropathy, neutropenia and hand-foot

syndrome, but were manageable.

Metaanalyses

Docetaxel alone or in combination

Metaanalysis; MBC

Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP, but not for OS and

ORR in MBC.



in metastatic breast cancer. J Cancer Res Clin Oncol. 2012 Feb;138(2):221-9.

2. Batist G, Ramakrishnan G, Sekhar Rao C et al (2001) Reduced cardiotoxicity and preserved antitumor efficacy of

liposome-encapsulted doxorubicin and cyclophosphamide compared with conventional doxorubicin and

cyclophosphamide in a randomized multicenter trial of metastatic breast cancer J. Clin Oncol 19: 1444-1454

MBC HER2 negative: Cytotoxic Therapy after Anthracycline Treatment* (10/18)


Consent:

Eribulin: 5++, 21+, 4+/-

1. Twelves C, Cortes J, Vahdat L, Olivo M, He Y, Kaufman PA, Awada A. Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies. Breast Cancer Res Treat. 2014;148:553-61.

Suggested after athracyclines (in alphabetical order): Capecitabine, Docetaxel, study-integrated experimental therapies,

Gemcitabine, Pegliposomales Doxorubicin, Paclitaxel and Vinorelbine.

As monotherapy after anthracyclin-pretreatment only Docetaxel improved OAS as compared to a standard treatment arm

in a prospective randomized trial in metastatic breast cancer (Nabholtz et al, 1999).

A Cochrane-metaanalysis of taxane treatment in metastatic breats cancer (Ghersi et al, 2003) shows a significant survival

advantage as compared to non-taxane-based therapies. There was no significant difference in QoL or treatment related

deaths. Final analysis of further end points was difficult due to significant heterogeneity of the single studies.

Indirect and direct comparisons of docetaxel and paclitaxel show a trend towards higher efficacy of docetaxel (Ghersi et

al, 2003; Ravdin et al, 2003). Due to different toxicity profiles of each substance individual indication is needed.

Docetaxel in Combination with Pegliposomal Doxorubicin was superior to docetaxel alone in a randomised phase III trial

by Sparano et al. It is one of the largest trials in this setting with 751 pts and demonstrated a clear PFS advantag fro m 9.8

vs 7 months without improving the OS. QoL was not different. Hand foot syndrome and mucositis were more common

wiht the combination.

2013

Nab-Paclitaxel

MBC HER2 negative: Cytotoxic Therapy After Taxane and Anthracycline Treatment (11/18)


1. Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377:914-23.

Nab Paclitaxel (100-150mg/m² d1,8,15,q28) has been tested in different populations. Not all pts received an anthracycline

and a taxane. It seems that a weekly dosing is superior to a 3 weekly dosing in terms of efficacy and side effects.

Suggested after anthracycline and taxane treatment (alphabetical order): capecitabine, study-integrated experimental

therapies, pegliposomal doxorubicin and vinorelbin.

Studies with more than 100 patients showed overall remissions of 9% and 20% using vinorelbine and pegylated liposomal

doxorubicin vs. capecitabine, respectively and a median survival of 9 months and 13 months.

Ixabepilone/Capecitabine vs. Capecitabine after anthracycline and taxane treatment in metastatic breast cancer is a phase

III randomised trial showing a significant improvement in PFS for the combination with a higher toxicity especialla in

neurotoxicity. Ixabepilone is not licensed in Germany; Thomas et al., JCO 25:5210-7 (2007)

Gemcitabine/vinorelbine vs. vinorelbine after anthracycline/taxane treatment in metastatic breast cancer; Martin et al.,

Lancet Oncol 8:219-25 (2007)

-38 pts treated with Gemcitabine/Cisplatin after anthracycline and taxane pretreatment as (neo)adjuvant, or 1st line met

therapy demonstrated a TTP of 5.2 months CI 3.6-6.8 and an OS of 19.5months CI 11.2-27.8 months. Kim JH; Cancer Res

Treat 2008; 40: 101-105

2013

Meta-analysis and evaluation

Eribulin is approved by the Food and Drug Administration for patients with previously treated metastatic breast cancer and

has demonstrated a survival benefit compared with standard treatment options in this setting.

Clin Ther. 2012 Jul;34(7):1467-73. doi: 10.1016/j.clinthera.2012.06.003. Epub 2012 Jun 25.

Eribulin mesylate (E7389): review of efficacy and tolerability in breast, pancreatic, head and neck, and non-small cell lung

cancer.

Scarpace SL.

New microtubule-targeting agents.

Review

The development of new microtubule-targeting agents helps to address the need for additional effective regimens for

patients progressing after standard treatment with anthracycline- and taxane-containing regimens.

Cortes J, Vidal M. Beyond taxanes: the next generation of microtubule-targeting agents. Breast Cancer Res Treat. 2012

Jun;133(3):821-30.

Triple Negative Metastatic Breast Cancer (TNBC: ER-, PR-, HER2-) (12/18)


Consent:

Carboplatin (vs. Docetaxel): 2++, 11+, 19+/-

Carboplatin in gBRCA mutation: 1++, 26+

Gemcitabin/Cisplatin (vs. GemPac): 1++, 18+, 10+/-

Carboplatin (vs. Docetaxel) / Carboplatin in gBRCA mutation:

1. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with

metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) Tutt A, Ellis P,

Kilburn L, Gilett C, Pinder S, Abraham J, Barrett S, Barrett-Lee P, Chan S, Cheang M, Fox L, Grigoriadis A,

Harper-Wynne C, Hatton M, Kernaghan S, Owen J, Parker P, Rahman N, Roylance R, Smith I, Thompson R, Tovey

H, Wardley A, Wilson G, Harries M, Bliss J. San Antonio Breast Cancer Symposium 2014; S3-01.

Gemcitabin/Cisplatin (vs. GemPac)

1. Gemcitabine with cisplatin or paclitaxel in metastatic triple-negative breast cancer. Xichun Hu, Binghe Xu, Li Cai,

Zhonghua Wang, Biyun Wang, Jian Zhang, Yuee Teng, Zhongsheng Tong, Yueyin Pan, Yongmei Yin, Changping

Wu, Zefei Jiang, Xiaojia Wang, Guyin Lou, Donggeng Liu, Jifeng Feng, Jianfeng Luo, Jiong

2. Wu, Zhimin Shao and Joseph Ragaz San Antonio Breast Cancer Symposium 2014; P3-10-02

Triple negative patients

J Clin Oncol 26: 2008 (May 20 suppl; abstr 1051)

Author(s):

B. Sirohi, M. Arnedos, S. Popat, S. Ashley, A. Nerurkar, G. Walsh, S. Johnston, I. E. Smith

Citation:

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement),

2007: 1086

Author(s):

J. W. Chia, P. Ang, H. See, Z. Wong, L. Soh, Y. Yap, N. Wong

2013

Met-TNBC Phase II (n=40; RR 35%, med OS 12 m, med TTP 6 m; 27% neutropenia °3/4)

1. Halim A, Wahba H. Cisplatin-ifosfamide combination chemotherapy in metastatic triple-negative, anthracycline- and

taxane-pretreated breast cancer patients; a phase II study. J BUON. 2012 Apr-Jun;17(2):254-8.

Bevacizumab Treatment in HER2-neg. Metastatic Breast Cancer (13/18)


Consent:

Cap+Bev as maintenance after Doc+Bev: 1++, 3+, 22+/-, 4-

2nd line as treatment through multiple lines: 19+/-, 4-

Cap+Bev as maintenance after Doc+Bev:

1. Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung

U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line

bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised,

open-label, phase 3 trial. Lancet Oncol. 2014;15:1351-60.

2nd line as treatment through multiple lines:

1. von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I,

Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus

chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent

or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label,

randomised phase 3 trial. Lancet Oncol. 2014;15:1269-78.

2. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.

N Engl J Med (2007) 357(26):2666–2676.

3. Miles D, Chan A, Luc Y, et al. Phase III Study of Bevacizumab Plus Docetaxel Compared With Placebo Plus

Docetaxel for the First-Line Treatment of Human Epidermal Growth Factor Receptor 2–NegativeMetastatic Breast

Cancer, J Clin Oncol 28:3239-3247, 2010

4. Roberts et al., RIBBON-1: Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With

or Without Bevacizumab for First-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative,

Locally Recurrent or Metastatic Breast Cancer, J Clin Oncol 29:1252-1260, 2011

5. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus

capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol (2005) 23(4):792–799.

6. Sledge G, Miller K, Moisa C, Gradishar W. Safety and efficacy of capecitabine (C) plus bevacizumab (B) as first-

line in metastatic breast cancer. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol

25, No. 18S (June 20 Supplement), 2007: 1013

7. Brufsky et al., RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the

Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human

Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer, J Clin Oncol 29:4286-4293. 201

2013

Individual trials

1. Taxanes +/- Bevacizumab

2. NabPaclitaxel vs Ixabepilone vs paclitaxel

1. Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Mayer EL, Naughton M, Layman RM, Carey LA,

Somer RA, Perez EA, Hudis C, Winer EP (2012) CALGB 40502/NCCTG N063H: Randomized phase III trial of

weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with

or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). J Clin

Oncol 30, 2012 (suppl; abstr CRA1002)

Review and opinion

Reddy S, Raffin M, Kaklamani V. Targeting angiogenesis in metastatic breast cancer. Oncologist. 2012;17(8):1014-26.

“Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.”

Side effects

Metaanalysis:

1. Cortes J, Calvo V, Ramírez-Merino N, O'Shaughnessy J, Brufsky A, Robert N, Vidal M, Muñoz E, Perez J, Dawood

S, Saura C, Di Cosimo S, González-Martín A, Bellet M, Silva OE, Miles D, Llombart A, Baselga J. Adverse events

risk associated with bevacizumab addition to breast cancer chemotherapy: a meta-analysis. Ann Oncol. 2012

May;23(5):1130-7.

First Line Therapy of HER2 Overexpressing Metastatic Breast Cancer (14/18)


Consent:

Taxanes + trastuzumab + everolimus: 4+/-, 21-, 5—

1. Giordano SH, Temin S, Kirshner JJ, Chandarlapaty S, Crews JR, Davidson NE, Esteva FJ, Gonzalez-Angulo AM,

Krop I, Levinson J, Lin NU, Modi S, Patt DA, Perez EA, Perlmutter J, Ramakrishna N, Winer EP. Systemic therapy

for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of

Clinical Oncology clinical practice guideline. J Clin Oncol. 2014;32:2078-99.

2013

Docetaxel + trastuzumab + pertuzumab (LoE 1bA AGO++)

Baselga et al., December 7, NEJM 2011

Side effects Pertuzumab

Skin rash

Pertuzumab is associated with a significant risk of rash, and the incidence varies among different tumor types. Prevention,

early recognition, and appropriate treatment of this rash may lead to improvement in patient quality of life, adherence to

therapy, and possibly optimize clinical outcomes.

1. Drucker AM, Wu S, Dang CT, Lacouture ME. Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a

meta-analysis. Breast Cancer Res Treat. 2012 Sep;135(2):347-54.

Paclitaxel + trastuzumab + pertuzumab (LoE 5D AGO+/-)

1st-Line chemotherapy* + trastuzumab (LoE 1bB AGO+)

(*taxanes; vinorelbine; paclitaxel/carboplatin; capecitabine/docetaxel)

1. Andersson M., Lidbrink E, Bjerre K. et al.: Phase III Randomized Study Comparing Docetaxel Plus Trastuzumab

With Vinorelbine Plus Trastuzumab As First-Line Therapy of Metastatic or Locally Advanced Human Epidermal

Growth Factor Receptor 2–Positive Breast Cancer: The HERNATA Study. DOI: 10.1200/JCO.2010.30.8213

2. Valero V., Forbes J., Pegramet M. D. et al.: Multicenter Phase III Randomized Trial Comparing Docetaxel and

Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With HER2-

Gene-Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens. DOI:

10.1200/JCO.2010.28.6450

3. Dawood S., Broglio K., Buzdaret AU. al.: Prognosis of Women With Metastatic Breast Cancer by HER2 Status and

Trastuzumab Treatment: An Institutional-Based Review. DOI: 10.1200/JCO.2008.19.9844

4. Robert N., Leyland-Jones B., Asmaret L. al.: Randomized Phase III Study of Trastuzumab, Paclitaxel, and

Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast

Cancer. DOI: 10.1200/JCO.2005.04.1764

5. Wardley AM., Pivot X., Morales-Vasquez F. et al.: Randomized Phase II Trial of First-Line Trastuzumab Plus

Docetaxel and Capecitabine Compared With Trastuzumab Plus Docetaxel in HER2-Positive Metastatic Breast

Cancer. DOI: 10.1200/JCO.2008.21.6531

Trastuzumab mono (LoE 2bB AGO+/-)

1. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2

monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after

chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-48.

2. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line

treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26.

Taxanes+ lapatinib (LoE 1baA AGO+/-)

1. Di Leo A, Gomez H, Aziz Z, et al. Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for

patients with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients. J Clin Oncol.

(2007 ASCO Annual Meeting Proceedings Part I) (2007) 25(18S):1011.

2. Gelmon KA, Boyle F, Kaufman B, Hunstman D et al. (2012) Open-Label phase III randomized controlled trial

comparing taxance-based chemotherapy (Tax) with lapatinib (L) or trastuzumab (T) as first-line therapy for women

with HER2+ metastatic breast cancer: Interim analysis (IA) of NCIC CTG MA.31/GSK EGF 108919. J Clin Oncol

30 (suppl, abstr LBA671), 2012

Trastuzumab + aromatase inihibitors (if ER+) (LoE 2bB AGO+/-)

1. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova

A, Revil C, Jones A: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal

women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast

cancer:results from the randomized phase III TAnDEM Study. J Clin Oncol 2009;27:5529–37

Lapatinib + aromatase inihibitors (if ER+) (LoE 2bB AGO+/-)

1. Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy

MJ, Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M: Lapatinib Combined With

Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive

Metastatic Breast Cancer. DOI: 10.1200/JCO.2009.23.3734

Second Line Therapy of HER2 Overexpressing Metastatic Breast Cancer (If Pretreatment with Trastuzumab)

(15/18)


T-DM1

1. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu

MW, Olsen S, Blackwell K. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med.

2012;367:1783-91.

2. Baselga et al., December 7, NEJM 2011

2013

Capecitabine + lapatinib (LoE 1b B AGO+)

1. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B,

Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B,

Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib

plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on

trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43.

2. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N

Engl J Med (2006) 355(26):2733–2743.

When compared against capecitabine alone, the addition of lapatinib has a cost-effectiveness ratio exceeding the threshold

normally used by NICE.

1. Delea TE, Tappenden P, Sofrygin O, Browning D, Amonkar MM, Karnon J, Walker MD, Cameron D. Cost-

effectiveness of lapatinib plus capecitabine in women with HER2+ metastatic breast cancer who have received prior

therapy with trastuzumab. Eur J Health Econ. 2012 Oct;13(5):589-603.

Trastuzumab + lapatinib (if CT not possible) (LoE 3b B AGO+)

Trastuzumab plus lapatinib vs lapatinib

Met-HER2posBC phase iii (2nd and further lines; n=291, HR-PFS =0.74, p=0.011; HR OS =0.74, p=0.026)

1. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J,

Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients

with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900

Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92.

2. O'Shaughnessy J, Blackwell KL, Burstein H, et al. A randomized study of lapatinib alone or in combination with

trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol

26: 2008 (May 20 suppl; abstr 1015).

TBP: 2nd-Line chemotherapy + trastuzumab (Treatment beyond progression) (LoE 2b D AGO +)

1. Von Minckwitz G, Zielinski C, Maarteense E, et al. Capecitabine vs. capecitabine + trastuzumab in patients with

HER2-positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG

26/BIG 3-05). J Clin Oncol 26: 2008 (May 20 suppl; abstr 1025).

Review

“Emerging evidence from randomized controlled trials supports the potential clinical utility of continuing trastuzumab-

based therapy beyond progression and supports the National Comprehensive Cancer Network recommendation to consider

this treatment approach. Future treatment of HER2-positive MBC may involve trastuzumab being used in successive

regimens in combination with other targeted therapies.”

1. Pegram M, Liao J. Trastuzumab treatment in multiple lines: current data and future directions. Clin Breast Cancer.

2012 Feb;12(1):10-8.

Taxane + trastuzumab + pertuzumab (LoE 5 D AGO +)

Any other 2nd-Line chemotherapy* + trastuzumab + pertuzumab (LoE 5 D AGO +/-)

Trastuzumab mono (DATEN?) (LoE 2b B AGO +/-)

2nd

line:

1. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2

monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after

chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-48.

1st line:

1. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line

treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-26.)

Trastuzumab + aromatase inihibitors (if ER+)(LoE 3b B AGO +)

1. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova

A, Revil C, Jones A: Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal

women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast

cancer:results from the randomized phase III TAnDEM Study. J Clin Oncol 2009;27:5529–37

Lapatinib + aromatase inihibitors (if ER+)(LoE 3b B AGO +)

1. Johnston S, Pippen Jr J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy

MJ, Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M: Lapatinib Combined With

Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor–Positive

Metastatic Breast Cancer. DOI: 10.1200/JCO.2009.23.3734

Further Lines of Therapy of HER2 Overexpressing Metastatic Breast Cancer (16/18)


2013

TBP: 2nd-line chemotherapy + trastuzumab + pertuzumab („treatment beyond progression“; with taxanes, vinorelbine,

paclitaxel/carboplatin, or capecitabine/docetaxel) (LoE 5 D AGO +/-)




2. Baselga, J. et al. (2010) Phase II trial of Pertuzumab and Trastuzumab in patients with human epidermal growth

factor receptor 2 – positive metastatic breast cancer that progessed during prior Trastuzumab therapy. JCO 28, 1138-

1144

Review

“Emerging evidence from randomized controlled trials supports the potential clinical utility of continuing trastuzumab-

based therapy beyond progression and supports the National Comprehensive Cancer Network recommendation to consider

this treatment approach. Future treatment of HER2-positive MBC may involve trastuzumab being used in successive

regimens in combination with other targeted therapies.”

1. Pegram M, Liao J. Trastuzumab treatment in multiple lines: current data and future directions. Clin Breast Cancer.

2012 Feb;12(1):10-8.

Capecitabine + lapatinib (LoE 2b B AGO +)







Engl J Med (2006) 355(26):2733–2743.

Trastuzumab + lapatinib (if CT not possible) (LoE 3bB AGO +)

1. Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J; Updated Survival

Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-

Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy. JCO 2010, 28: 1124-1130



26: 2008 (May 20 suppl; abstr 1015).

Experimental anti-HER2-regimen (including trastuzumab-Emtansine, T-DM1) (LoE 5D AGO +)

EMILIA

1. Blackwell K. et al. (2012) Primary Results From EMILIA, a Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs

Capecitabine and Lapatinib in

2. HER2-Positive Locally Advanced or Metastatic Breast Cancer Previously Treated With Trastuzumab and a Taxane.

ASCO 2012

3. Sachdev JC, Jahanzeb M. Blockade of the HER family of receptors in the treatment of HER2-positive metastatic

breast cancer. Clin Breast Cancer. 2012 Feb;12(1):19-29.

4. Baselga et al., Dec

Lapatinib in HER2-positive Metastatic Breast Cancer (17/18)


Anthracycline and Taxane and Trastuzumab pre-treatment







Engl J Med (2006) 355(26):2733–2743.






26: 2008 (May 20 suppl; abstr 1015).

5. Blackwell KL, Burstein HJ, Sledge GW, Stein S, Ellis C, Casey M, Baselga J, O'Shaughnessy J; Updated Survival

Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-

Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy. JCO 2010, 28: 1124-1130

http://www.ncbi.nlm.nih.gov/pubmed/18188694?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum














































Trastuzumab naive patients: first line therapy

1. Di Leo A, Gomez H, Aziz Z, et al. Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for

patients with metastatic breast cancer: a phase III randomized, double-blind study of 580 patients. J Clin Oncol.

(2007 ASCO Annual Meeting Proceedings Part I) (2007) 25(18S):1011.

Brain metastases (radioresistance)

1. Lin NU, Carey LA, Liu MC, et al. Phase II trial of lapatinib for brain metastases in patients with human epidermal

growth factor receptor 2-positive breast cancer. J Clin Oncol. 2008;26:1993-9.

Immunodiagnostic Tests and Immunotherapy (18/18)


No references

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