Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection.
OBJECTIVE
The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the predominant histologic pattern-lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)-present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT).


METHODS
Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis.


RESULTS
A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01).


CONCLUSIONS
The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain. ming.tsao@uhn.ca.
Ming-Sound
MS
Tsao
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Sophie
S
Marguet
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Gwénaël
G
Le Teuff
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Sylvie
S
Lantuejoul
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Frances A
FA
Shepherd
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Lesley
L
Seymour
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Robert
R
Kratzke
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Stephen L
SL
Graziano
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Helmut H
HH
Popper
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Rafael
R
Rosell
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Jean-Yves
JY
Douillard
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Thierry
T
Le-Chevalier
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Jean-Pierre
JP
Pignon
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Jean-Charles
JC
Soria
Ming-Sound Tsao and Frances A. Shepherd, Princess Margaret Cancer Centre, University Health Network, and University of Toronto, Toronto; Lesley Seymour, NCIC Clinical Trials Group and Queen's University, Kingston, Ontario, Canada; Sophie Marguet, Gwénaël Le Teuff, Thierry Le-Chevalier, Jean-Pierre Pignon, and Jean-Charles Soria, Gustave Roussy, Villejuif; Sylvie Lantuejoul and Elisabeth M. Brambilla, Inserm U823, Centre Hospitalier Universitaire de Grenoble, Institut Albert Bonniot, Université Joseph Fourier, Grenoble; Jean-Yves Douillard, Centre René Gauducheau, Saint-Herblain, Nantes, France; Robert Kratzke, University of Minnesota, Minneapolis, MN; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Helmut H. Popper, Institute of Pathology, University Medical School of Graz, Graz, Austria; and Rafael Rosell, Catalan Institute of Oncology, Barcelona, Spain.
Elisabeth M
EM
Brambilla
D000230:Adenocarcinoma / Q000145:classification* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000368:Aged; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D015996:Survival Rate