Under the background of the rapid development of medicine, the continuous development and improvement of multimodal treatment programs have improved the survival rate of LABC[8,9], but because clinicians make different clinical treatment decisions for different molecular types of LABC, the survival outcomes of each subtype are different. Exploring the effects of clinical treatment decisions on long-term survival outcomes of different molecular types of LABC can promote an accurate understanding of different treatment options by clinicians, which also has a certain impact on the development of individualized treatment.
Table 2
OS and BCSS at 5 years after breast-conserving and total mastectomy for overall LABC and different molecular subtypes
|
OS(%)
|
P values
|
BCSS(%)
|
P values
|
breast conserving
|
total mastectomy
|
|
breast conserving
|
total mastectomy
|
|
Total
|
77.6
|
68.4
|
< 0.001
|
84.6
|
77.2
|
< 0.001
|
Luminal A
|
79.9
|
72.3
|
< 0.001
|
87.5
|
81.5
|
< 0.001
|
Luminal B
|
79.3
|
70.8
|
0.015
|
83.1
|
77.1
|
0.058
|
Triple Negative
|
61.0
|
47.5
|
< 0.001
|
68.4
|
56.2
|
< 0.001
|
HER2 enriched
|
75.7
|
67.2
|
< 0.001
|
80.5
|
75.2
|
0.004
|
Three positive
|
84.9
|
75.5
|
< 0.001
|
91.8
|
82.1
|
< 0.001
|
IIB
|
81.8
|
75.8
|
< 0.001
|
91.5
|
86.7
|
< 0.001
|
IIIA
|
80.6
|
72.6
|
< 0.001
|
85.9
|
80.6
|
< 0.001
|
IIIB
|
62.1
|
58.4
|
0.032
|
79.3
|
71.0
|
< 0.001
|
IIIC
|
69.5
|
59.4
|
< 0.001
|
74.6
|
67.6
|
< 0.001
|
Table 3
Baseline comparison between LABC breast-conserving and total mastectomy patients
|
breast-conserving
|
total mastectomy
|
P Value
|
Age n(%)
|
|
|
0.233
|
< 55
|
2684(36.3)
|
6492(35.5)
|
|
≥ 55
|
4715(63.7)
|
11806(64.5)
|
|
Stage n(%)
|
|
|
< 0.001
|
IIB
|
1258(17.0)
|
2092(11.4)
|
|
IIIA
|
4249(57.4)
|
9486(51.8)
|
|
IIIB
|
568(7.7)
|
2295(12.5)
|
|
IIIC
|
1324(17.9)
|
4425(24.3)
|
|
T n(%)
|
|
|
< 0.001
|
T0
|
4(0.0)
|
10(0.1)
|
|
T1
|
1652(22.3)
|
1701(9.3)
|
|
T2
|
2646(35.8)
|
5620(30.7)
|
|
T3
|
2483(33.6)
|
8149(44.5)
|
|
T4
|
598(8.1)
|
2785(15.2)
|
|
TX
|
16(0.2)
|
33(0.2)
|
|
N n(%)
|
|
|
< 0.001
|
N0
|
1557(21.0)
|
2694(14.7)
|
|
N1
|
1045(14.2)
|
4138(22.6)
|
|
N2
|
3473(46.9)
|
7041(38.5)
|
|
N3
|
1324(17.9)
|
4425(24.2)
|
|
Grade n(%)
|
|
|
0.036
|
I
|
734(9.9)
|
1620(8.9)
|
|
II
|
3097(41.9)
|
7705(42.1)
|
|
III
|
3542(47.9)
|
8889(48.6)
|
|
IV
|
26(0.3)
|
84(0.4)
|
|
Radiation n(%)
|
|
|
< 0.001
|
No
|
122(1.6)
|
391(2.1)
|
|
Unknown
|
2289(30.9)
|
7317(40.0)
|
|
Yes
|
4988(67.5)
|
10590(57.9)
|
|
Chemotherapy n(%)
|
|
|
0.729
|
NO/Unknown
|
1906(25.8)
|
4753(26.0)
|
|
Yes
|
5493(74.2)
|
13545(74.0)
|
|
This study found that the Luminala-type LABC had a better degree of differentiation compared to other types, which was consistent with the conclusion of Liu ZF et al[10].We know that more differentiated tumor cells represent a lower degree of malignancy, and the degree of malignancy determines its prognosis to a certain extent. This study also found that the LuminalA type has the best prognosis among the four subtypes of LuminalA, LuminalB, TNBC and HER2 enriched, which is consistent with the conclusions of relevant literature [11–13],which is directly related to the different gene expression patterns of different molecular subtypes of breast cancer [14–17].It has been reported that the inhibitor of growth (ING) present in cells can affect the regulation of biological functions and biochemical pathways after interacting with many other proteins [18].For example, the expression rate of nuclear ING3 in Luminal breast cancer is higher than that in HER2 enriched and TNBC breast cancer. At the same time, it is also concluded that the nucleus of ING3 is positively correlated with the status of ER and PR [19].We know that the expression status of ER and PR determines the treatment plan of breast cancer to a certain extent, which verifies that the treatment method of Luminala-type LABC is mainly endocrine. This study identified TNBC LABC as the type with the worst prognosis among subtypes, which is consistent with the findings of Karen S Johnson et al [13].Studies have shown that this is the result of multiple gene regulation[17].Hachim IY pointed out in an article published in 2017 that the expression of the EPHA4 protein of Eph receptor family is associated with poor tumor clinical outcomes, EPHA4 is involved in cell migration in breast cancer cells by regulating TGFβ. The expression of EPHA4 in TNBC breast cancer is significantly higher than other subtypes, which may be related to the higher local recurrence, metastasis, and drug resistance of TNBC breast cancer[20].Xu J also pointed out that a large number of lncrnas are abnormally expressed in patients with breast cancer from TNBC, indicating that lncrnas have a high diagnostic value for TNBC breast cancer [21].
In this study, TPBC was introduced, which was different from the traditional breast cancer classification. By analyzing the survival rate of LABC with different molecular subtypes, it was found that the prognosis of TPBC LABC was the best among various molecular subtypes. Regarding the emergence of TPBC, Vici P et al. stated in an article published in 2015 that: "In HER-2 positive tumors, HR status may define two different subtypes with different clinical behaviors and different sensitivities to anticancer drugs" [22].Dieci MV et al., in an article published in 2020, also pointed out that TPBC was regarded as an independent subtype in breast cancer. It may be beneficial in the formation of individualized treatment for patients [23], why is TPBC the type with the best prognosis? Reviewing the relevant literature, we know that TPBC is HR+/HER2 + breast cancer[24–26].Similarly, with the understanding of breast cancer, we have learnt that trastuzumab has become the first-line drug for HER2 + breast cancer since its advent in 1998[29],and subsequent relevant literature has also proved that the discovery of targeted drugs has improved the survival rate of HER2 + breast cancer, which has greatly improved the survival of these patients to a certain extent[30–32].Through the analysis of the above data, we suspect that the reason for the higher survival rate of TPBC than other types is the result of the dual use of endocrine and targeted therapy. However, we found that the treatment of TPBC is far more complex than we imagined, and it is not a simple 1 + 1 = 2 mode. Since TPBC has both estrogen receptor and HER2 signaling pathways, some studies have shown that the coexistence of these two pathways will cause bidirectional interference of treatment[22,33,34],which can induce the development of resistance to endocrine therapy and anti-HER2 therapy[35].Relevant literature indicates that the addition of trastuzumab in the treatment of some TPBCs does not lead to better survival outcomes [36],and the biological behavior of these patients is more inclined to the Luminal type, and the degree of response to trastuzumab is lower[26].
With the development of modern medicine and the exploration of new research, the treatment of TPBC is constantly updated. Anti-her2 targeting and combination endocrine therapy has become a common way to treat TPBC[38,39].CLEOPATRA studies have shown that pertuzumab + trastuzumab + docetaxel significantly improves OS in HER2 + breast cancer compared to placebo + trastuzumab + docetaxel[40–41].PERTAIN (NCT01491737) study showed that Pertuzumab + trastuzumab + Aromatase Inhibitor, Compared with trastuzumab + AI, Progression free survival (PFS) of TPBC LABC could be significantly improved[42]. The latest the results of ALTERNATIVE study also confirmed that, compared to the single target, anti-HER2 bidirectional block can significantly benefit TPBC clinically[43].As to whether chemotherapy should be performed before TPBC treatment, studies have shown that some TPBC PFS can benefit from pertuzumab + trastuzumab + AI without chemotherapy[43,44].In conclusion, the emergence of targeted drugs greatly improves the clinical benefits of TPBC patients, and the application of dual-target + AI combined drugs also provides a more effective treatment plan for TPBC LABC patients. With the continuous understanding of diseases, precision therapy has become a general trend in medical development, and it is also a big challenge for us to explore the advantageous population of the dual target + AI combined drug therapy model.
In this study, the population was divided into two subgroups using the cutoff age of 55 years. OS and BCSS were found to be significantly lower in patients aged 55 years of age or older than in those aged less than 55 years. Reviewing the relevant literature, we found that the relationship between age and prognosis has been controversial. Studies have shown that in early breast cancer, young patients show higher rates of recurrence and mortality compared with elderly patients[45]. The study found that at baseline of the population: Luminal breast cancer accounts for 69.3% of all breast cancer. Partridge AH and his team reported in J Clin Oncol in 2015 that the effect of age on survival in early-stage breast cancer is dependent on breast cancer subtype. And for Luminal breast cancer, young women have a better prognosis than older women [46].Van de Water W et al. 2012 concluded in an article published in JAMA that in postmenopausal breast cancer patients with HR (+) age is positively correlated with disease-specific mortality[47].An article published in 2022 on the correlation between mortality after recurrence of breast cancer and age at initial diagnosis in China pointed out that patients older age at initial diagnosis face a higher risk of death after recurrence[48].At present, there is no literature report on the age of LABC and the risk of death,This study found that the OS and BCSS of patients with LABC ≥ 55 years old were significantly lower than those of patients with LABC < 55 years old. Although there is with no relevant data to clearly point out the specific relationship between age and prognosis, the exploration of the relationship between the two has never stopped, This is both a great challenge and a great project to achieve personalized treatment.
This study found that the breast-conserving survival rate of overall LABC and LABC with different molecular types was higher than that of total mastectomy and modified radical mastectomy, and it was statistically significant. To explore the reasons for this, we compared the baseline population of breast-conserving surgery, total mastectomy, and modified radical mastectomy. The results showed that: The population of breast-conserving surgery is concentrated in patients with early tumor stage and small tumor diameter, which indicates that clinicians choose breast-conserving surgery for patients with low LABC load during preoperative evaluation, which is consistent with the conclusion of Kouwenberg CAE et al.[49].In 2016, van Maaren MC et al. found that for patients with NI-N2 breast cancer, the long-term survival rate of breast-conserving surgery was higher than that of total mastectomy[50].An article published by Veronesi U in 2002 on the long-term follow-up after breast-conserving and radical mastectomy concluded that for the long-term survival of early breast cancer, Breast-conserving surgery is superior to modified radical mastectomy[51].Another article by van Maaren MC also pointed out that for early breast cancer, the 10-year survival rate and relative survival rate of breast-conserving surgery were improved compared with mastectomy[52].On the other hand, the wide use of neoadjuvant therapy makes the indications of breast-conserving surgery more extensive [53], which promotes clinicians to increase the selectivity of patients. Relevant literature has shown that cancer cell components of tumor cells can interact with their surrounding stromal cells and Inflammatory cells to form a new microenvironment, namely Inflammatory tumor microenvironment (TME). The article points out: Cells within the TME are highly plastic and can continuously change their phenotypic and functional characteristics[54].The article published by Mhaidly R et al., 2020, pointed out that there is a type of cell in TNM that positively affects tumor growth, metastasis, remodelling, and other characteristics, namely: Cancer-associated fibroblasts (CAF), such cells are highly heterogeneous and play different functions in tumors [55].As mentioned in Costa A's article, a large number of studies have found that cafs-s1 fibroblast subsets achieve immunosuppression by attracting T lymphocytes and increasing the survival of CD4 + CD25 + T lymphocytes [56].All of these can explain to some extent why the survival rate of breast-conserving surgery is higher than that of total resection and modified radical surgery. However, due to the complexity of its genes, it is not a simple project to truly understand the reasons, and continuing to explore the reasons may be helpful to improve the quality of life and survival time of patients with LABC in the future.
In conclusion, this study showed that the 5-year survival rate of TPBC breast cancer was higher than that of other groups. In the selective population, the OS and BCSS of LABC patients undergoing breast-conserving surgery were significantly better than those of mastectomy. When comparing OS and BCSS of LABC patients with different molecular subtypes and stages, breast-conserving surgery was still superior to mastectomy. Although Luminala-type LABC still can not give up chemotherapy, but for highly differentiated, NO stage TPBC LABC can selectively exempt chemotherapy. The emergence of targeted drugs not only benefits the survival of HER2 + breast cancer, but also the use of dual target + AI combination drugs also benefits TPBC LABC patients in clinical practice. However, more prospective studies are still needed to explore and confirm the advantages of various treatment regimens, so as to provide a more favorable treatment mode for achieving individualized treatment.