Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3.
Two recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2-overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment.



Archival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing.



Biomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47% of BOLERO-1 and 41% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway status. When analyzing combined data sets of both studies, everolimus was associated with a decreased hazard of progression in patients with PIK3CA mutations (hazard ratio [HR], 0.67; 95% CI, 0.45 to 1.00), PTEN loss (HR, 0.54; 95% CI, 0.31 to 0.96), or hyperactive PI3K pathway (HR, 0.67; 95% CI, 0.48 to 0.93). Patients with wild-type PIK3CA (HR, 1.10; 95% CI, 0.83 to 1.46), normal PTEN (HR, 1.00; 95% CI, 0.80 to 1.26), or normal PI3K pathway activity (HR, 1.19; 95% CI, 0.87 to 1.62) did not derive PFS benefit from everolimus.



This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2-positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus.
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ. Fabrice.ANDRE@gustaveroussy.fr.
Fabrice
F
André
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Sara
S
Hurvitz
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Angelica
A
Fasolo
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Ling-Ming
LM
Tseng
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Guy
G
Jerusalem
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Sharon
S
Wilks
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Ruth
R
O'Regan
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Claudine
C
Isaacs
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Masakazu
M
Toi
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Howard
H
Burris
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Wei
W
He
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Douglas
D
Robinson
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Markus
M
Riester
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Tetiana
T
Taran
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
David
D
Chen
Fabrice André, Institut Gustav Roussy, INSERM Unit U981, Université Paris Sud, Villejuif, France; Sara Hurvitz and Dennis Slamon, University of California, Los Angeles, Los Angeles, CA; Angelica Fasolo, San Raffaele Scientific Institute, Milan, Italy; Ling-Ming Tseng, National Yang Ming University, Taipei, Taiwan; Guy Jerusalem, University of Liège, Liege, Belgium; Sharon Wilks, Cancer Care Center of South Texas, San Antonio, TX; Ruth O'Regan, University of Wisconsin Carbone Cancer Center, Madison, WI; Claudine Isaacs, Georgetown University, Washington DC; Masakazu Toi, Kyoto University, Sakyo-ku, Kyoto, Japan; Howard Burris, Sarah Cannon Research Institute, Nashville, TN; Wei He, Douglas Robinson, and Markus Riester, Novartis Institutes for BioMedical Research, Cambridge, MA; and Tetiana Taran and David Chen, Novartis Pharmaceuticals Corporation, East Hanover, NJ.
Dennis
D
Slamon
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human