HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design, Patients, and Samples
2.2. Histopathological Review
2.3. ER, PR, and Ki67 Protein Expression Analysis Using Immunohistochemistry (IHC)
2.4. HER2 Status Assessment
2.5. Molecular Analysis
2.5.1. DNA and RNA Extraction
2.5.2. DNA Sequencing
2.5.3. RNA Sequencing and Transcriptomic Analysis
2.6. Statistical Analysis
3. Results
3.1. Clinicopathological Characteristics of Patients and Carcinomas
3.2. Genomic Profiles
3.3. Transcriptomic Profiles
3.3.1. ERBB2 mRNA Expression
3.3.2. Gene Expression of the PI3K-AKT, JAK-STAT, and the MAPK Pathway
3.4. Global Gene Expression and Phenotypic Profiles within the Different Pathways, and the Impact of PIK3CA Activating Mutations
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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p-Values | |||||||
---|---|---|---|---|---|---|---|
H2L (n = 62) | HER2-Negative (n = 20) | HER2-Positive (n = 43) | All | 0+ vs. HER2-Positive | 0+ vs. H2L | HER2-Positive vs. H2L | |
n (%) | n (%) | n (%) | |||||
Patient age | 0.9054 | ||||||
Mean ± SD | 65.0 ± 12.6 | 65.3 ± 12.8 | 64.0 ± 13.5 | ||||
Median [min–max] | 67.0 [34.0–93.0] | 68.5 [36.0–91.0] | 64.0 [37.0–89.0] | ||||
Patient menopausal status | 0.4422 | ||||||
Peri/premenopausal | 10 (16.1) | 5 (25.0) | 11 (25.6) | ||||
Postmenopausal | 52 (83.9) | 15 (75.0) | 32 (74.4) | ||||
Tumor size (US, mm) | 0.126 | ||||||
Mean ± SD | 18.9 ± 14.1 | 14.9 ± 12.3 | 18.7 ± 11.4 | ||||
Median [min–max] | 15.0 [5.0–70.0] | 11.3 [3.5–50.0] | 15.0 [4.0–58.0] | ||||
Node status (US) | 0.5397 | ||||||
N0 | 59 (95.2) | 18 (90.0) | 38 (88.4) | ||||
N1 | 3 (4.8) | 2 (10.0) | 4 (9.3) | ||||
N3 | 0 (0) | 0 (0) | 1 (2.3) | ||||
Multifocality | 0.5519 | ||||||
Unifocal | 50 (80.6) | 18 (90.0) | 37 (86.0) | ||||
Bifocal | 12 (19.4) | 2 (10.0) | 6 (14.0) | ||||
Tumor size (clinical, mm) | 0.8995 | ||||||
Mean ± SD | 18.1 ± 11.9 | 18.1 ± 11.7 | 18.9 ± 11.6 | ||||
Median [min–max] | 15.0 [4.5–70.0] | 15.5 [6.0–55.0] | 15.0 [5.8–58.0] | ||||
Node status | 0.0146 | 0.0497 | 0.0531 | 0.6476 | |||
pN0 | 41 (66.1) | 9 (45.0) | 34 (79.1) | ||||
pN1 | 19 (30.6) | 6 (30.0) | 7 (16.3) | ||||
pN2 | 2 (3.2) | 4 (20.0) | 2 (4.7) | ||||
pN3 | 0 (0) | 1 (5.0) | 0 (0) | ||||
E&E grade | 0.0005 | 0.0005 | 0.9656 | 0.0017 | |||
I | 25 (40.3) | 10 (50.0) | 3 (7.0) | ||||
II | 31 (50.0) | 10 (50.0) | 31 (72.1) | ||||
III | 6 (9.7) | 0 (0) | 9 (20.9) | ||||
Glandular differentiation | 0.1734 | ||||||
1 | 3 (4.8) | 1 (5.0) | 0 (0) | ||||
2 | 30 (48.4) | 9 (45.0) | 14 (32.6) | ||||
3 | 29 (46.8) | 10 (50.0) | 29 (67.4) | ||||
Nuclear grade | 0.0348 | 0.1398 | 1 | 0.0756 | |||
1 | 2 (3.2) | 0 (0) | 0 (0) | ||||
2 | 54 (87.1) | 19 (95.0) | 31 (72.1) | ||||
3 | 6 (9.7) | 1 (5.0) | 12 (27.9) | ||||
Mitosis score | 0.0003 | 0.0001 | 0.0651 | 0.0537 | |||
1 | 39 (62.9) | 19 (95.0) | 15 (34.9) | ||||
2 | 14 (22.6) | 1 (5.0) | 18 (41.9) | ||||
3 | 9 (14.5) | 0 (0) | 10 (23.3) | ||||
Mitotic index (/mm²) | 0.0002 | 0.0002 | 0.4007 | 0.0042 | |||
Mean ± SD | 2.9 ± 2.6 | 1.8 ± 1.6 | 4.8 ± 3.2 | ||||
Median [min–max] | 1.8 [0.4–10.5] | 0.9 [0.4–6.6] | 4.4 [0.4–15.1] | ||||
Histologic subtype | 0.5616 | ||||||
Micropapillary | 2 (3.2) | 0 (0) | 1 (2.3) | ||||
Mucinous | 0 (0) | 1 (5.0) | 0 (0) | ||||
NST | 57 (91.9) | 18 (90.0) | 41 (95.3) | ||||
NST + micropapillary | 3 (4.8) | 1 (5.0) | 1 (2.3) | ||||
Lymphovascular emboli | 0.9027 | ||||||
No | 41 (66.1) | 13 (65.0) | 30 (69.8) | ||||
Yes | 21 (33.9) | 7 (3.0) | 13 (30.2) | ||||
sTIL (%) | 0.1407 | ||||||
Mean ± SD | 7.0 ± 7.6 | 8.2 ± 9.3 | 10.6 ± 9.6 | ||||
Median [min–max] | 5.0 [1.0–50.0] | 4.0 [1.0–30.0] | 5.0 [1.0–40.0] | ||||
sTIL (≤10%) | 0.0507 | ||||||
No | 8 (12.9) | 4 (20.0) | 14 (32.6) | ||||
Yes | 54 (87.1) | 16 (80.0) | 29 (67.4) | ||||
sTILs (>40%) | 1 | ||||||
No | 61 (98.4) | 20 (100.0) | 42 (97.7) | ||||
Yes | 1 (1.6) | 0 (0) | 1 (2.3) | ||||
ER (I × %) | 0.5524 | ||||||
Mean ± SD | 285.2 ± 34.0 | 280.0 ± 41.9 | 277.3 ± 43.2 | ||||
Median [min–max] | 300.0 [180.0–300.0] | 300.0 [160.0–300.0] | 300.0 [140.0–300.0] | ||||
PR (I × %) | 0.0281 | 0.0757 | 0.7856 | 0.0567 | |||
Mean ± SD | 198.4 ± 99.4 | 212.3 ± 100.2 | 151.0 ± 110.4 | ||||
Median [min–max] | 210.0 [0.0–300.0] | 247.5 [20.0–300.0] | 140.0 [0.0–300.0] | ||||
Ki67 (%) | <0.0001 | 0.0002 | 0.3919 | 0.0003 | |||
n | 62 | 20 | 42 * | ||||
Mean ± SD | 15.7 ± 10.2 | 14.4 ± 13.5 | 23.8 ± 11.4 | ||||
Median [min–max] | 14.5 [2.0–60.0] | 11.0 [2.0–60.0] | 21.5 [5.0–60.0] |
p-Values | |||||||||
---|---|---|---|---|---|---|---|---|---|
HER2 DE (n = 22) | HER2 0+ (n = 20) | HER2 1+ (n = 20) | HER2 2+ NA (n = 20) | HER2 2+ WA (n = 20) | HER2 3+ (n = 23) | All | DE vs. 0+ | DE vs. 1+ | |
n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | ||||
Patient age | 0.1129 | ||||||||
Mean ± SD | 69.5 ± 9.1 | 65.3 ± 12.8 | 66.7 ± 11.5 | 58.3 ± 14.6 | 63.3 ± 13.3 | 64.7 ± 13.9 | |||
Median [min–max] | 70.5 [50.0–85.0] | 68.5 [36.0–91.0] | 71.0 [42.0–83.0] | 53.0 [34.0–93.0] | 62.0 [37.0–84.0] | 64.0 [38.0–89.0] | |||
Patient menopausal status | 0.5713 | ||||||||
Peri/premenopausal | 2 (9.1%) | 5 (25.0%) | 3 (15.0%) | 5 (25.0%) | 6 (30.0%) | 5 (21.7%) | |||
Postmenopausal | 20 (90.9%) | 15 (75.0%) | 17 (85.0%) | 15 (75.0%) | 14 (70.0%) | 18 (78.3%) | |||
Tumor size (US, mm) | 0.0533 | ||||||||
Mean ± SD | 20.2 ± 14.1 | 14.9 ± 12.3 | 13.4 ± 8.4 | 22.9 ± 17.3 | 16.6 ± 8.3 | 20.5 ± 13.4 | |||
Median [min–max] | 15.0 [6.0–70.0] | 11.3 [3.5–50.0] | 11.0 [5.0–38.0] | 16.5 [6.0–70.0] | 14.5 [4.0–30.0] | 15.0 [7.0–58.0] | |||
Node status (US) | 0.3889 | ||||||||
N0 | 19 (86.4%) | 18 (90.0%) | 20 (100.0%) | 20 (100.0%) | 18 (90.0%) | 20 (87.0%) | |||
N1 | 3 (13.6%) | 2 (10.0%) | 0 (0.0%) | 0 (0.0%) | 2 (10.0%) | 2 (8.7%) | |||
N3 | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (4.3%) | |||
Multifocality | 0.1893 | ||||||||
Unifocal | 18 (81.8%) | 18 (90.0%) | 14 (70.0%) | 18 (90.0%) | 15 (75.0%) | 22 (95.7%) | |||
Bifocal | 4 (18.2%) | 2 (10.0%) | 6 (30.0%) | 2 (10.0%) | 5 (25.0%) | 1 (4.3%) | |||
Tumor size (clinical, mm) | 0.6973 | ||||||||
Mean ± SD | 17.5 ± 6.7 | 18.1 ± 11.7 | 14.6 ± 7.3 | 22.1 ± 17.9 | 17.8 ± 8.7 | 19.9 ± 13.7 | |||
Median [min–max] | 16.0 [8.0–30.0] | 15.5 [6.0–55.0] | 12.3 [4.5–32.0] | 17.2 [5.0–70.0] | 14.8 [7.0–35.0] | 15.0 [5.8–58.0] | |||
Node status | 0.1845 | ||||||||
pN0 | 12 (54.5%) | 9 (45.0%) | 14 (70.0%) | 15 (75.0%) | 15 (75.0%) | 19 (82.6%) | |||
pN1 | 9 (40.9%) | 6 (30.0%) | 6 (30.0%) | 4 (20.0%) | 4 (20.0%) | 3 (13.0%) | |||
pN2 | 1 (4.5%) | 4 (20.0%) | 0 (0.0%) | 1 (5.0%) | 1 (5.0%) | 1 (4.3%) | |||
pN3 | 0 (0.0%) | 1 (5.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |||
E&E grade | <0.0001 | 0.2706 | 0.0577 | ||||||
I | 3 (13.6%) | 10 (50.0%) | 12 (60.0%) | 10 (50.0%) | 2 (10.0%) | 1 (4.3%) | |||
II | 17 (77.3%) | 10 (50.0%) | 7 (35.0%) | 7 (35.0%) | 14 (70.0%) | 17 (73.9%) | |||
III | 2 (9.1%) | 0 (0.0%) | 1 (5.0%) | 3 (15.0%) | 4 (20.0%) | 5 (21.7%) | |||
Glandular differentiation | 0.0166 | 1 | 0.398 | ||||||
1 | 1 (4.5%) | 1 (5.0%) | 0 (0.0%) | 2 (10.0%) | 0 (0.0%) | 0 (0.0%) | |||
2 | 5 (22.7%) | 9 (45.0%) | 12 (60.0%) | 13 (65.0%) | 7 (35.0%) | 7 (30.4%) | |||
3 | 16 (72.7%) | 10 (50.0%) | 8 (40.0%) | 5 (25.0%) | 13 (65.0%) | 16 (69.6%) | |||
Nuclear grade | 0.0349 | 1 | 1 | ||||||
1 | 0 (0.0%) | 0 (0.0%) | 1 (5.0%) | 1 (5.0%) | 0 (0.0%) | 0 (0.0%) | |||
2 | 20 (90.9%) | 19 (95.0%) | 18 (90.0%) | 16 (80.0%) | 17 (85.0%) | 14 (60.9%) | |||
3 | 2 (9.1%) | 1 (5.0%) | 1 (5.0%) | 3 (15.0%) | 3 (15.0%) | 9 (39.1%) | |||
Mitosis score | <0.0001 | 0.0156 | 0.2428 | ||||||
1 | 10 (45.5%) | 19 (95.0%) | 17 (85.0%) | 12 (60.0%) | 6 (30.0%) | 9 (39.1%) | |||
2 | 9 (40.9%) | 1 (5.0%) | 3 (15.0%) | 2 (10.0%) | 9 (45.0%) | 9 (39.1%) | |||
3 | 3 (13.6%) | 0 (0.0%) | 0 (0.0%) | 6 (30.0%) | 5 (25.0%) | 5 (21.7%) | |||
Mitotic index (/mm²) | <0.0001 | 0.0065 | 0.1072 | ||||||
Mean ± SD | 4.2 ± 2.6 | 1.8 ± 1.6 | 2.4 ± 2.7 | 2.0 ± 2.1 | 4.9 ± 3.3 | 4.6 ± 3.3 | |||
Median [min–max] | 4.1 [0.9–10.5] | 0.9 [0.4–6.6] | 1.3 [0.4–9.6] | 0.7 [0.4–7.1] | 5.0 [0.4–11.3] | 4.0 [0.5–15.1] | |||
Histologic subtype | 0.0988 | ||||||||
Micropapillary | 2 (9.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (5.0%) | 0 (0.0%) | |||
Mucinous | 0 (0.0%) | 1 (5.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |||
NST | 17 (77.3%) | 18 (90.0%) | 20 (100.0%) | 20 (100.0%) | 19 (95.0%) | 22 (95.7%) | |||
NST + micropapillary | 3 (13.6%) | 1 (5.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (4.3%) | |||
Lymphovascular emboli | 0.1758 | ||||||||
No | 11 (50.0%) | 13 (65.0%) | 17 (85.0%) | 13 (65.0%) | 12 (60.0%) | 18 (78.3%) | |||
Yes | 11 (50.0%) | 7 (35.0%) | 3 (15.0%) | 7 (35.0%) | 8 (40.0%) | 5 (21.7%) | |||
sTIL (%) | 0.0429 | 1 | 0.6094 | ||||||
Mean ± SD | 6.4 ± 5.8 | 8.2 ± 9.3 | 10.0 ± 10.6 | 4.7 ± 4.7 | 10.2 ± 11.2 | 11.0 ± 8.3 | |||
Median [min–max] | 5.0 [1.0–20.0] | 4.0 [1.0–30.0] | 6.5 [1.0–50.0] | 2.0 [1.0–20.0] | 5.0 [1.0–40.0] | 10.0 [2.0–25.0] | |||
sTIL (≤10%) | 0.1314 | ||||||||
No | 3 (13.6%) | 4 (20.0%) | 4 (20.0%) | 1 (5.0%) | 5 (25.0%) | 9 (39.1%) | |||
Yes | 19 (86.4%) | 16 (80.0%) | 16 (80.0%) | 19 (95.0%) | 15 (75.0%) | 14 (60.9%) | |||
sTILs (>40%) | 0.4702 | ||||||||
No | 22 (100.0%) | 20 (100.0%) | 19 (95.0%) | 20 (100.0%) | 19 (95.0%) | 23 (100.0%) | |||
Yes | 0 (0.0%) | 0 (0.0%) | 1 (5.0%) | 0 (0.0%) | 1 (5.0%) | 0 (0.0%) | |||
ER (I × %) | 0.0299 | 0.9142 | 1 | ||||||
Mean ± SD | 292.7 ± 22.5 | 280.0 ± 41.9 | 292.0 ± 23.5 | 270.0 ± 47.4 | 290.0 ± 30.8 | 266.3 ± 49.8 | |||
Median [min–max] | 300.0 [200.0–300.0] | 300.0 [160.0–300.0] | 300.0 [200.0–300.0] | 300.0 [180.0–300.0] | 300.0 [200.0–300.0] | 300.0 [140.0–300.0] | |||
PR (I × %) | 0.0407 | 0.833 | 1 | ||||||
Mean ± SD | 180.5 ± 102.5 | 212.3 ± 100.2 | 184.0 ± 95.5 | 232.5 ± 95.7 | 133.1 ± 119.6 | 166.5 ± 101.8 | |||
Median [min–max] | 170.0 [0.0–300.0] | 247.5 [20.0–300.0] | 160.0 [30.0–300.0] | 270.0 [10.0–300.0] | 130.0 [0.0–300.0] | 160.0 [20.0–300.0] | |||
Ki67 (%) | <0.0001 | 0.0175 | 0.0011 | ||||||
n | 22 | 20 | 20 | 20 | 20 | 22 * | |||
Mean ± SD | 20.8 ± 10.4 | 14.4 ± 13.5 | 10.6 ± 5.7 | 15.2 ± 11.1 | 20.0 ± 7.8 | 27.2 ± 13.1 | |||
Median [min–max] | 20.0 [8.0–60.0] | 11.0 [2.0–60.0] | 9.0 [5.0–25.0] | 13.5 [2.0–40.0] | 20.0 [5.0–40.0] | 25.0 [8.0–60.0] |
Controls | p-Value | |||||
---|---|---|---|---|---|---|
Gene | Mutation Impact * | H2L (n = 62) | HER2-Negative (n = 20) | HER2-Positive (n = 40) | All | H2L vs. HER2-Positive |
n (%) | n (%) | n (%) | ||||
PIK3CA | Gain of function | 28 (45.2) | 8 (40.0) | 6 (15.0) | 0.0063 | 0.0048 |
AKT1 | Gain of function | 5 (8.1) | 0 | 0 | 0.1104 | - |
PTEN | Loss of function | 1 (1.6) | 0 | 1 (2.5) | 1 | - |
TP53 | Loss of function | 3 (4.8) | 0 | 12 (30.0) | 0.0003 | 0.0028 |
BRCA1 | - | 0 | 0 | 0 | - | - |
BRCA2 | Loss of function | 3 (4.8) | 0 | 2 (5.0) | 0.854 | - |
PALB2 | - | 0 | 0 | 0 | - | - |
ARID1A | Loss of function | 0 | 0 | 1 (2.5) | 0.4918 | - |
KRAS | - | 0 | 0 | 0 | - | - |
NRAS | - | 0 | 0 | 0 | - | - |
BRAF | - | 0 | 0 | 0 | - | - |
Controls | ||||||||
---|---|---|---|---|---|---|---|---|
Gene | Mutation Impact * | HER2 DE (n = 22) | HER2 0+ (n = 20) | HER2 1+ (n = 20) | HER2 2+ NA (n = 20) | HER2 2+ WA (n = 20) | HER2 3+ (n = 20) | p-Value |
n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | |||
PIK3CA | Gain of function | 8 (36.4) | 8 (40.0) | 10 (50.0) | 10 (50.0) | 5 (25.0) | 1 (5.0) | 0.0227 |
AKT1 | Gain of function | 0 | 0 | 2 (10.0) | 3 (15) | 0 | 0 | 0.0368 |
PTEN | Loss of function | 0 | 0 | 0 | 1 (5.0) | 1 (5.0) | 0 | 0.7019 |
TP53 | Loss of function | 1 (4.5) | 0 | 0 | 2 (10.0) | 4 (20.0) | 8 (40.0) | 0.0004 |
BRCA1 | - | 0 | 0 | 0 | 0 | 0 | 0 | |
BRCA2 | Loss of function | 2 (9.1) | 0 | 0 | 1 (5.0) | 1 (5.0) | 1 (5.0) | 0.8997 |
PALB2 | - | 0 | 0 | 0 | 0 | 0 | 0 | |
ARID1A | Loss of function | 0 | 0 | 0 | 0 | 0 | 1 (5.0) | 0.8197 |
KRAS | - | 0 | 0 | 0 | 0 | 0 | 0 | |
NRAS | - | 0 | 0 | 0 | 0 | 0 | 0 | |
BRAF | - | 0 | 0 | 0 | 0 | 0 | 0 |
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André, C.; Bertaut, A.; Ladoire, S.; Desmoulins, I.; Jankowski, C.; Beltjens, F.; Charon-Barra, C.; Bergeron, A.; Richard, C.; Boidot, R.; et al. HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity. Cancers 2024, 16, 2009. https://doi.org/10.3390/cancers16112009
André C, Bertaut A, Ladoire S, Desmoulins I, Jankowski C, Beltjens F, Charon-Barra C, Bergeron A, Richard C, Boidot R, et al. HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity. Cancers. 2024; 16(11):2009. https://doi.org/10.3390/cancers16112009
Chicago/Turabian StyleAndré, Céline, Aurélie Bertaut, Sylvain Ladoire, Isabelle Desmoulins, Clémentine Jankowski, Françoise Beltjens, Céline Charon-Barra, Anthony Bergeron, Corentin Richard, Romain Boidot, and et al. 2024. "HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity" Cancers 16, no. 11: 2009. https://doi.org/10.3390/cancers16112009
APA StyleAndré, C., Bertaut, A., Ladoire, S., Desmoulins, I., Jankowski, C., Beltjens, F., Charon-Barra, C., Bergeron, A., Richard, C., Boidot, R., & Arnould, L. (2024). HER2-Low Luminal Breast Carcinoma Is Not a Homogenous Clinicopathological and Molecular Entity. Cancers, 16(11), 2009. https://doi.org/10.3390/cancers16112009