Clinical trial NCT00553358: Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study
Official title: Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) Study: A Randomised, Multicenter Open-label Phase III Study of Neoadjuvant Lapatinib, Trastuzumab and Their Combination Plus Paclitaxel in Women With HER2/ErbB2 Positive Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neoplasms, Breast
Keywords: Lapatinib
ErbB2+
Early Breast Cancer
Neoadjuvant
breast carcinoma
breast cancer
breast lump
HER2 positive metastatic breast cancer
breast cancer positive for human epidermal growth factor receptor 2 (HER2) HER2 positive metastatic breast cancer
breast cancer progression
estrogen-receptor (ER) positive(+) breast cancer
Paget's disease
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Breast International Group
name: SOLTI Breast Cancer Research Group
First posted: 2007-11-04
Enrollment: 455
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: This is a randomised, open label multicenter Phase III study comparing the efficacy of neoadjuvant lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer.

Patients will be randomised to receive either: lapatinib 1500 mg daily, trastuzumab 4 mg/kg intravenous (IV) load followed by 2 mg/kg IV weekly, or lapatinib 1000 mg daily with trastuzumab 4 mg/kg IV load followed by 2 mg/kg IV weekly for a total of 6 weeks. After this biological window, patients on monotherapy arms will continue on the same targeted therapy plus weekly paclitaxel 80 mg/m\^2 for a further 12 weeks, up to definitive surgery. In the combination arm, patients will receive lapatinib 750 mg daily in combination with trastuzumab 2 mg/kg IV plus weekly paclitaxel 80mg/m\^2 IV for a further 12 weeks, up to definitive surgery. After surgery, patients will receive three courses of adjuvant chemotherapy with 5-Fluorouracil Epirubicin Cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant setting for a further 34 weeks (in the combination arm, lapatinib dose will be 1000 mg daily in combination with trastuzumab). The planned total duration of the anti-HER2 therapy one year.

Primary objective is to evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in patients with HER2/ErbB2 overexpressing or amplified operable breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib, trastuzumab plus paclitaxel.

Detailed description: This was a parallel group, three-arm, randomized, multicenter, open-label phase III study. The study compared the efficacy and tolerability of neoadjuvant lapatinib and paclitaxel, versus trastuzumab and paclitaxel, versus the combination of lapatinib with trastuzumab and paclitaxel given as neoadjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. Subjects were randomized to receive lapatinib, trastuzumab or lapatinib plus trastuzumab for a total of 6 weeks. After this biological window, subjects continued on the same targeted therapy plus weekly paclitaxel for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). Paclitaxel could be initiated at Week 4 if there is evidence of progressive disease (PD) at that time. Within 6 weeks after surgery, subjects received 3 cycles of adjuvant 5-flourouracil, epirubicin and cyclophosphamide (FEC) followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy).

After completing 52 weeks of (neo-)/adjuvant anti-HER2 therapy, subjects were scheduled to attend post-treatment follow-up every 3 months during the first year (months 12, 15, 18, 21, and 24), every 6months in Years 3 to 5 inclusive, and annually thereafter up to Year 10. Each subject was to be followed for 10 Years. All subjects were to be followed for EFS and OS up to 10 years from last subject randomized.

Eligibility criteria: Inclusion Criteria:

* Female gender;
* Age ≥18 years;
* Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1
* Histologically confirmed invasive breast cancer:
* Primary tumour greater than 2 cm diameter, measured by clinical examination and mammography or echography,
* Any N,
* No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed);
* Over expression and/or amplification of HER2 in the invasive component of the primary tumour \[Wolff et al 2006\] and confirmed by a certified laboratory prior to randomisation
* Known hormone receptor status.
* Haematopoietic status:
* Absolute neutrophil count ≥ 1,5 x 10\^9/L,
* Platelet count ≥ 100 x 10\^9/L,
* Hemoglobin at least 9 g/dl,
* Hepatic status:
* Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (\< 2 x ULN) is allowed,
* Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN,
* Alkaline phosphatase ≤ 2.5 times ULN,
* Renal status:
* Creatinine ≤ 2.0 mg/dL,
* Cardiovascular:
* Baseline left ventricular ejection fraction (LVEF) ³ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,
* Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization (For women of childbearing potential)
* Fertile patients must use effective contraception (barrier method - condoms, diaphragm - also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed)
* Signed informed consent form (ICF)
* Patient accepts to make available tumour samples for submission to central laboratory to conduct translational studies as part of this protocol

Exclusion Criteria:

* Received any prior treatment for primary invasive breast cancer;
* Previous (less than 10 years) or current history of malignant neoplasms, except for curatively treated:
* Basal and squamous cell carcinoma of the skin;
* Carcinoma in situ of the cervix.
* Patients with a prior malignancy diagnosed more than 10 years prior to randomisation may enter the study. Patients must have been curatively treated with surgery alone. Radiation therapy or systemic therapy (chemotherapy or endocrine) are NOT permitted. Prior diagnoses of breast cancer or melanoma are excluded.
* Diagnosis of inflammatory breast cancer;
* Bilateral cancer;
* This criterion has been deleted from the protocol Version 1. Patients with multi-focal cancer are no longer excluded.
* Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, transmural myocardial infarction, uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen;
* Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety;
* Unresolved or unstable, serious adverse events from prior administration of another investigational drug;
* Active or uncontrolled infection;
* Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
* Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);
* Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients;
* Pregnant or lactating women;
* Concomitant use of CYP3A4 inhibitors or inducers

Primary outcomes:
measure: Number of Participants With Pathological Complete Response (pCR) at the Time of Surgery
timeFrame: Weeks 20 to 22
Secondary outcomes:
measure: Number of Participants With Overall Response at Week 6
timeFrame: Week 6
measure: Overall Response at the Time of Surgery
timeFrame: Time of surgery (Weeks 20 to 22)
measure: Number of Participants With Negative Lymph Nodes at the Time of Surgery
timeFrame: Time of surgery (Weeks 20 to 22)
measure: Number of Participants With Actual Indicated Surgery
timeFrame: At surgery (Weeks 20 to 22)
measure: Mean Change From Baseline in Tumor Size at Week 6 and at Surgery
timeFrame: Week 6 and surgery (Weeks 20 to 22)
measure: Number of Participants Starting Paclitaxel Before Completing 6 Weeks of Treatment With Either Lapatinib or Trastuzumab
timeFrame: Week 6
measure: Event-free Survival (EFS) - Median Clinical Follow-up
timeFrame: From randomization up to approximately year 10
measure: Event-free Survival (EFS) - Events and Censoring
timeFrame: From randomization up to approximately year 10
measure: Overall Survival (OS) - Median Survival Follow-up
timeFrame: From randomization up to approximately year 10
measure: Overall Survival (OS) - Deaths and Censoring
timeFrame: From randomization up to approximately year 10
measure: Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Median Clinical Follow-up (EFS Landmark Population)
timeFrame: up to year 10
measure: Assess Associations Between Locoregional Pathological Complete Response (pCR) and Event-free Survival (EFS) - Number of Participants With EFS Events (EFS Landmark Population)
timeFrame: up to year 10
measure: Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Median Clinical Follow-up (OS Landmark Population)
timeFrame: up to year 10
measure: Assess Associations Between Locoregional Pathological Complete Response (pCR) and and Overall Survival (OS) - Number of Participants Who Died (OS Landmark Population)
timeFrame: up to year 10
measure: To Assess Safety Via a Comparison of the Three Treatment Arms - to Measure On-treatment Primary Cardiac Endpoints
timeFrame: Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 31 weeks.
measure: Metabolic Response Rate Determined by Positron Emission Tomography/Computed Tomography (PET/CT)
timeFrame: Week 2 and Week 6
measure: Percentage of Participants With the Indicated Biomarker Expression - PIK3CA.
timeFrame: Baseline
measure: Percentage of Participants With the Indicated Biomarker Expression - PTEN.
timeFrame: Baseline
measure: Ratio (95% CI) of Geometric Means in p95HER2 Expression in HR Positive Patients With pCR vs no pCR
timeFrame: Baseline
measure: Percentage of Participants With Circulating Tumor Cells (CTC) in the Bloodstream
timeFrame: Measurement performed at one or more of the time points: baseline, week 2 or week 18
Other outcomes:
Locations:
city: Berazategui
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Quilmes
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Tucuman
country: Argentina
facility: Novartis Investigative Site
city: Brussels
country: Belgium
facility: Novartis Investigative Site
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Santo Andre
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: São Paulo
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Brno
country: Czechia
facility: Novartis Investigative Site
city: Novy Jicin
country: Czechia
facility: Novartis Investigative Site
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Bayonne
country: France
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Le Mans
country: France
facility: Novartis Investigative Site
city: Levallois-Perret
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Reims
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Karlsruhe
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Fuerth
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Nuernberg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Fuerstenwalde
country: Germany
facility: Novartis Investigative Site
state: Brandenburg
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Rostock
country: Germany
facility: Novartis Investigative Site
state: Mecklenburg-Vorpommern
city: Stralsund
country: Germany
facility: Novartis Investigative Site
state: Mecklenburg-Vorpommern
city: Celle
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Hannover
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Dortmund
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Witten
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Halle
country: Germany
facility: Novartis Investigative Site
state: Sachsen-Anhalt
city: Kiel
country: Germany
facility: Novartis Investigative Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Kowloon
country: Hong Kong
facility: Novartis Investigative Site
city: Wanchai
country: Hong Kong
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Bangalore
country: India
facility: Novartis Investigative Site
city: Hyderabad
country: India
facility: Novartis Investigative Site
city: Mumbai
country: India
facility: Novartis Investigative Site
city: Nagpur
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Pune
country: India
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Genova
country: Italy
facility: Novartis Investigative Site
state: Liguria
city: Lecco
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Monza
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Sondrio
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Trento
country: Italy
facility: Novartis Investigative Site
state: Trentino-Alto Adige
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Songpa-gu, Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Vilnius
country: Lithuania
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Karachi
country: Pakistan
facility: Novartis Investigative Site
city: Lima
country: Peru
facility: Novartis Investigative Site
city: Lima
country: Peru
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Cluj-Napoca
country: Romania
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
state: Gauteng
city: Athlone Park, Amanzimtoti
country: South Africa
facility: Novartis Investigative Site
city: Capital Park
country: South Africa
facility: Novartis Investigative Site
city: Parktown
country: South Africa
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Girona
country: Spain
facility: Novartis Investigative Site
city: Lerida
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Mataro
country: Spain
facility: Novartis Investigative Site
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
city: Toledo
country: Spain
facility: Novartis Investigative Site
city: Torrevieja (Alicante)
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: Changhua
country: Taiwan
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Chernivtsi
country: Ukraine
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Kharkiv
country: Ukraine
facility: Novartis Investigative Site
city: Kiev
country: Ukraine
facility: Novartis Investigative Site
city: Krivoy Rog
country: Ukraine
facility: Novartis Investigative Site
city: Kyiv
country: Ukraine
facility: Novartis Investigative Site
city: Lviv
country: Ukraine
facility: Novartis Investigative Site
city: Odessa
country: Ukraine
facility: Novartis Investigative Site
city: Simferopol
country: Ukraine
facility: Novartis Investigative Site
city: Epping
country: United Kingdom
facility: Novartis Investigative Site
state: Essex
city: Bournemouth
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Baselga J, Piccart M, Gelber R, di CosimoS, Viale G, Koehler M, Rojo F. Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study [BIG 1-06 /solti/EGF106903]: a phase III translational study for HER2-overexpressing early breast cancer. [Lancet]. 2012;S140-6736(11):
citation: Chumsri S, Li Z, Serie DJ, Norton N, Mashadi-Hossein A, Tenner K, Brauer HA, Warren S, Danaher P, Colon-Otero G, Partridge AH, Carey LA, Hilbers F, Van Dooren V, Holmes E, Di Cosimo S, Werner O, Huober JB, Dueck AC, Sotiriou C, Saura C, Moreno-Aspitia A, Knutson KL, Perez EA, Thompson EA. Adaptive immune signature in HER2-positive breast cancer in NCCTG (Alliance) N9831 and NeoALTTO trials. NPJ Breast Cancer. 2022 May 24;8(1):68. doi: 10.1038/s41523-022-00430-0.
citation: Pizzamiglio S, Cosentino G, Ciniselli CM, De Cecco L, Cataldo A, Plantamura I, Triulzi T, El-Abed S, Wang Y, Bajji M, Nuciforo P, Huober J, Ellard SL, Rimm DL, Gombos A, Daidone MG, Verderio P, Tagliabue E, Di Cosimo S, Iorio MV. What if the future of HER2-positive breast cancer patients was written in miRNAs? An exploratory analysis from NeoALTTO study. Cancer Med. 2022 Jan;11(2):332-339. doi: 10.1002/cam4.4449. Epub 2021 Dec 17.
citation: Powles RL, Redmond D, Sotiriou C, Loi S, Fumagalli D, Nuciforo P, Harbeck N, de Azambuja E, Sarp S, Di Cosimo S, Huober J, Baselga J, Piccart-Gebhart M, Elemento O, Pusztai L, Hatzis C. Association of T-Cell Receptor Repertoire Use With Response to Combined Trastuzumab-Lapatinib Treatment of HER2-Positive Breast Cancer: Secondary Analysis of the NeoALTTO Randomized Clinical Trial. JAMA Oncol. 2018 Nov 1;4(11):e181564. doi: 10.1001/jamaoncol.2018.1564. Epub 2018 Nov 8.
citation: Fumagalli D, Venet D, Ignatiadis M, Azim HA Jr, Maetens M, Rothe F, Salgado R, Bradbury I, Pusztai L, Harbeck N, Gomez H, Chang TW, Coccia-Portugal MA, Di Cosimo S, de Azambuja E, de la Pena L, Nuciforo P, Brase JC, Huober J, Baselga J, Piccart M, Loi S, Sotiriou C. RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial. JAMA Oncol. 2017 Feb 1;3(2):227-234. doi: 10.1001/jamaoncol.2016.3824.
citation: Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, de Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol. 2015 Jul;1(4):448-54. doi: 10.1001/jamaoncol.2015.0830.
citation: Nuciforo PG, Aura C, Holmes E, Prudkin L, Jimenez J, Martinez P, Ameels H, de la Pena L, Ellis C, Eidtmann H, Piccart-Gebhart MJ, Scaltriti M, Baselga J. Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status. Ann Oncol. 2015 Jul;26(7):1494-500. doi: 10.1093/annonc/mdv175. Epub 2015 Apr 7.
citation: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. doi: 10.1016/S1470-2045(14)70320-1. Epub 2014 Aug 14.
citation: Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer. 2012 Jul 12;12(8):553-63. doi: 10.1038/nrc3309.
citation: Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gomez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horvath Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. doi: 10.1016/S0140-6736(11)61847-3. Epub 2012 Jan 17.