Abstract
Purpose
This study aims to explore whether neoadjuvant chemotherapy with immunotherapy (NACI) leads to different tumor shrinkage patterns, based on magnetic resonance imaging (MRI), compared to neoadjuvant chemotherapy (NAC) alone in patients with triple-negative breast cancer (TNBC). Additionally, the study investigates the relationship between tumor shrinkage patterns and treatment efficacy was investigated.
Methods
This retrospective study included patients with TNBC patients receiving NAC or NACI from January 2019 until July 2021 at our center. Pre- and post-treatment MRI results were obtained for each patient, and tumor shrinkage patterns were classified into three categories as follows: 1) concentric shrinkage (CS); 2) diffuse decrease; and 3) no change. Tumor shrinkage patterns were compared between the NAC and NACI groups, and the relevance of the patterns to treatment efficacy was assessed.
Results
Of the 99 patients, 65 received NAC and 34 received NACI. The CS pattern was observed in 53% and 20% of patients in the NAC and NACI groups, respectively. Diffuse decrease pattern was observed in 36% and 68% of patients in the NAC and NACI groups. The association between the treatment regimens (NAC and NACI) and tumor shrinkage patterns was statistically significant (p = 0.004). The postoperative pathological complete response (pCR) rate was 45% and 82% in the NAC and NACI groups (p < 0.001), respectively. In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). All tumor shrinkage patterns were associated with achieved a high pCR rate in the NACI group.
Conclusion
Our study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than that following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC treated with NACI.
Trial Registration
ClinicalTrials.gov Identifier: NCT04909554
Keywords: Immunotherapy, Magnetic Resonance Imaging, Neoadjuvant Therapy, Triple Negative Breast Neoplasms
INTRODUCTION
Currently, breast cancer has surpassed lung cancer as the most prevalent malignant tumor globally, posing a grave threat to the well-being of women [1]. Triple-negative breast cancer (TNBC) accounts for 10%–15% of all breast cancer subtypes and has a relatively poor prognosis [2]. Currently, neoadjuvant chemotherapy (NAC) has become the standard treatment plan and has become increasingly important role in the comprehensive care of locally advanced breast cancer [3,4]. The pathological complete response (pCR) rate following NAC serves as a favorable prognostic indicator for breast cancer patients [5,6,7]. Currently, significant progress is being made in immunotherapy for the treatment of breast cancer. In recent years, considerable progress has been made in the pharmacological treatment of TNBC, particularly with immune checkpoint inhibitors. Prior research has demonstrated a significantly enhanced in the pCR rate for early-stage TNBC when immunotherapy is combined with chemotherapy, relative to that with chemotherapy alone [8,9].
Traditional chemotherapy uses chemical drugs to prevent cancer cell proliferation and infiltration and ultimately eradicate tumor cells. In contrast to traditional chemotherapy, the main mechanism of immunotherapy comprises the induction of a change in the tumor microenvironment and the use of immune cells to recognize and kill tumor cells, thereby inhibiting tumor growth. The immunotherapy–chemotherapy combination functions through the chemotherapy-induced apoptosis of cancer cells and the release of numerous cancer antigens, which decrease the tumor burden while removing immunosuppressive cells and modulating the immune system microenvironment. Therefore, immunotherapy combined with chemotherapy can strengthen the body’s anticancer effect in the body [10,11].
In patients with breast cancer patients, magnetic resonance imaging (MRI) is the most commonly used adjuvant test to assess the tumor response to NAC. After NAC, breast tumors exhibit varying degrees and different patterns of shrinkage [12]. The shrinkage patterns refer to the changing trend of in the overall tumor shape and three-dimensional volume of the tumor compared with before and after treatment and can be categorized as concentric shrinkage (CS), diffuse regression, stable disease, and progressive disease. Radiologists assessed shrinkage patterns by determining the changes in the morphology and size of residual lesions before and after NAC. Currently, shrinkage is generally divided into the CS mode and the non-concentric shrinkage (NCS) mode . Previous studies have shown that TNBC is more likely to present with CS. Current research also indicates that CS after NAC is associated with pCR and that pCR after NAC is beneficial for the long-term survival of patients with TNBC patients [13]. The shrinkage pattern of breast tumors thus holds crucial importance for the evaluation of the residual tumor burden, assessing treatment efficacy, surgical selection, and predicting prognosis [14].
Although there have been previous studies on the tumor shrinkage patterns post-NAC, the pattern achieved after immunotherapy combined with chemotherapy remains unknown. Given that immunotherapy and chemotherapy have distinct antitumor mechanisms, it is plausible to assume the existence of distinct shrinkage patterns between neoadjuvant chemotherapy with immunotherapy (NACI) and NAC can be assumed; however, it is not clear whether this shrinkage pattern is related to pCR.
In this retrospective study, we investigated whether the tumor shrinkage patterns differ, based on MRI, between patients with TNBC who received NACI and those who received NAC and the correlation between shrinkage patterns and treatment efficacy.
METHODS
Patients and materials
We retrospectively enrolled patients with the TNBC patients receiving NAC or NACI between January 2019 and July 2021 at our hospital. The following criteria were used to enroll patients: 1) age ≥ 18 years; 2) biopsy-confirmed noninflammatory invasive TNBC with no distant metastatic disease; 3) clinical-stage of I–III and previously untreated; 4) no missing baseline clinicopathological factors; and 5) breast MRI examination was conducted at baseline, after the first cycle of neoadjuvant therapy and preoperatively using a field strength magnet of 1.5 T or 3.0 T. The exclusion criteria encompassed the following: 1) absence of baseline characteristics and 2) inadequate or unavailable MR images. The patterns of tumor shrinkage comprised the primary endpoint. The diagnosis of TNBC aligned with the guidelines set forth by the College of American Pathologists and the American Society of Clinical Oncology. The cutoff value for estrogen receptor and progesterone receptor was defined as 1% [15]. Human epidermal growth factor receptor 2 (HER-2) status was determined by categorizing tumors with an immunohistochemistry (IHC) staining score of 0 to 1+ representing HER-2 negative, and 3+ representing HER-2 positive. Tumors with an IHC score of 2+ were subjected to additional in situ hybridization (ISH) testing to confirm their HER-2 status. A nonamplified ISH result indicated a negative HER-2 status, whereas amplified results indicated a positive HER-2 status. The pCR definition criteria comprised ypT0/is ypN0 (no invasive residual disease in the breast or nodes; noninvasive breast residuals allowed) [16].
Neoadjuvant therapy regimen
In this retrospective study, patients were enrolled and scheduled to follow the standard chemotherapy regimen outlined in the National Comprehensive Cancer Network Breast Cancer Guidelines. Preoperative chemotherapy regimens, as recommended by qualified oncologists were taxane-based, anthracycline-based, or a combination of the two. Patients in the NAC group received the NAC regimens as follows: 1) non-anthracycline-based regimen: TCb chemotherapeutic regimen (75 mg/m2 docetaxel and carboplatin with an area under the curve [AUC] of six, every three weeks); 2) anthracycline-based regimen the EC followed by T regimen (90 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide every three weeks for four cycles, followed by a four-cycle period of 100 mg/m2 docetaxel every three weeks). Patients in the NACI group received neoadjuvant therapy regimens as follows: 1) non-anthracycline-based regimen four cycles of programmed cell death 1 (PD-1) inhibitor at a dose of 200 mg every three weeks plus TCb chemotherapy regimen (75 mg/m2 docetaxel and carboplatin with an AUC of six, every three weeks); 2) anthracycline-based regimen four cycles of PD-1 inhibitor at a dose of 200 mg every three weeks plus TCb-AC (75 mg/m2 docetaxel and carboplatin every three weeks, followed by 90 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide every three weeks for four cycles).
This study was approved by the Ethics Committee of Guangdong Provincial People's Hospital (NCT04909554). As our study had a retrospective in design and did not involve any additional interventions, the requirement for informed consent was waived.
Determination of tumor regression patterns
Patients underwent a breast MRI examination using a 1.5 T or 3.0 T field strength magnet within 1 week before the biopsy, after the first cycle of neoadjuvant therapy, and preoperatively. The tumor shrinkage patterns were determined based on the MR image after the first cycle of neoadjuvant therapy, compared to the baseline MRI. Each patient was subjected to the acquisition of two imaging sequences; namely, diffusion-weighted imaging and fat-suppressed T2-weighted imaging. All tumor shrinkage patterns were interpreted, based on MRI, by two breast radiologists with 10 years of experience. The tumor level, morphology, and relative enhancement were assessed based on baseline MR images, MR images after the first cycle of neoadjuvant therapy, and early and late enhancement based on preoperative MR images. The tumor grade assessment involved determination of the largest diameter in three reconstruction planes (sagittal, axial, and coronal) during both the early and late enhancement phases.
We divided into three groups as follows: 1) CS; 2) diffuse decrease; and 3) no change. The CS pattern was defined as the largest diameter being reduced, and no non-enlarged lesions or small masses around the main tumor were seen during the neoadjuvant therapy regimen. Other shrinkage patterns, such as diffuse decrease and no change, could not be classified as concentric type (referred to as NCS patterns) (Figure 1).
Figure 1. Tumor shrinkage patterns after neoadjuvant treatment. (A) Primary cancer. (B) Concentric shrinkage. (C) Diffuse decrease. (D) No change.
Three experienced breast pathologists, each with over 15 years of experience in interpreting postoperative breast specimens, independently examined the specimens and determined the pCR based on the hematoxylin and eosin-stained slides. Consensus among the three pathologists was reached to mitigate potential errors arising from interobserver variability.
Statistical analysis
All clinicopathologic and MRI findings were compared between patients with and without pCR using the χ2 test or Fisher’s exact test, as appropriate. For univariable and multivariable analysis, logistic regression analyses were used. Statistical analysis was performed using statistical analysis software (Predictive Analytics Software, Version 21.0.0; SPSS, Chicago, IL, USA), and p < 0.05 was considered significant.
RESULTS
Between January 2019 and July 2021, 99 patients from Guangdong Provincial People's Hospital were retrospectively enrolled. Patient characteristics are shown in Table 1. Patient and treatment features were balanced in both groups. The median age of the 99 patients was 47.8 years (range 25–69 years). In total, 75% of the patients had T1 or T2 tumors, and 51% had axillary lymph node involvement. Moreover, 69% and 31% of patients had clinical stage II and III disease, and 30% and 70% of patients received breast-conserving surgery (BCS) and mastectomy, respectively. In total, 40% and 59% of patients exhibited nuclear grades 1–2 and 3, respectively. In total, 32% and 68% of patients were treated with non-anthracycline-based and anthracycline-based regimens, respectively.
Table 1. Baseline characteristics.
| Parameter | Overall (n = 99) | NACI (n = 34) | NAC (n = 65) | p-value | |
|---|---|---|---|---|---|
| Age (yr) | |||||
| Median | 47.8 | 46.8 | 48.8 | ||
| Range | 35–69 | 30–67 | 25–69 | ||
| ≤ 50 | 55 (56) | 21 (62) | 34 (52) | 0.401 | |
| > 50 | 44 (44) | 13 (38) | 31 (48) | ||
| Tumor size | 0.330 | ||||
| T1–T2 | 74 (75) | 23 (68) | 51 (78) | ||
| T3–T4 | 25 (25) | 11 (32) | 14 (22) | ||
| Lymph node metastases | 0.291 | ||||
| Negative | 49 (49) | 14 (41) | 35 (54) | ||
| Positive | 50 (51) | 20 (59) | 30 (46) | ||
| Clinical stage* | 0.067 | ||||
| II | 68 (69) | 19 (54) | 49 (75) | ||
| III | 31 (31) | 15 (46) | 16 (25) | ||
| Nuclear grade | 0.958 | ||||
| 1–2 | 40 (40) | 14 (41) | 26 (40) | ||
| 3 | 58 (59) | 20 (59) | 38 (58) | ||
| NAC regimen | 0.375 | ||||
| Non-anthracycline based | 32 (32) | 13 (38) | 19 (29) | ||
| Anthracycline based | 67 (68) | 21 (62) | 46 (71) | ||
| Breast surgery | 0.648 | ||||
| Breast-conserving surgery | 30 (30) | 9 (26) | 21 (32) | ||
| Mastectomy | 69 (70) | 25 (74) | 44 (68) | ||
| Therapeutic effect | < 0.001 | ||||
| pCR | 57 (58) | 28 (82) | 29 (45) | ||
| Non-pCR | 42 (42) | 6 (18) | 36 (55) | ||
Values are presented as number (%).
NACI = neoadjuvant chemotherapy with immunotherapy; NAC = neoadjuvant chemotherapy; pCR = pathological complete response
*Based on the 8th American Joint Committee on Cancer staging system.
Of the 99 study patients, 65 received NAC, and 34 received NACI. The CS patterns observed in the NAC and NACI groups were 53% and 20%, respectively. The diffuse decrease patterns observed in the NAC and NACI groups were 36% and 68%, respectively (Figure 2). The NACI and NAC regimens were significantly correlated with the tumor shrinkage pattern (p = 0.004), and the postoperative pCR rates were 45% and 82% in the NAC and NACI groups, respectively (p < 0.001). In the NAC group, 53% of patients with the CS pattern and 36% of those with the diffuse decrease pattern achieved pCR, and CS pattern was a significantly associated with pCR (p = 0.001). In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). Patients with all tumor shrinkage patterns had a high pCR rate in the NACI group (Table 2).
Figure 2. Typical magnetic resonance images of the patterns of tumor shrinkage in two patients.
(A, B) A 46-year-old woman with breast cancer treated with NACI. MR images show a typical diffuse decrease shrinkage pattern. The tumor appeared as a 7.0-cm round circumscribed mass on baseline MRI examination (A). MRI showed a residual tumor of 2.5-cm after one cycle (B). (C, D) A 32-year-old woman with breast cancer treated with NAC. MR images show a typical simple concentric shrinkage pattern. The tumor appeared as a 5.1-cm round circumscribed mass on baseline MRI examination (C). The MRI showed a 1.2-cm residual tumor after one cycle (D).
NACI = neoadjuvant chemotherapy with immunotherapy; MR = magnetic resonance; MRI = magnetic resonance imaging; NAC = neoadjuvant chemotherapy.
Table 2. Relationship between tumor shrinkage patterns and a pathological complete response.
| Parameter | pCR | Non-pCR | p-value | |
|---|---|---|---|---|
| NAC | 0.001 | |||
| CS | 23 (35.4) | 12 (18.5) | ||
| Diffuse decrease | 5 (7.7) | 18 (27.7) | ||
| No change | 1 (1.5) | 6 (9.2) | ||
| NACI | 0.903 | |||
| CS | 6 (17.7) | 1 (2.9) | ||
| Diffuse decrease | 19 (55.9) | 4 (11.8) | ||
| No change | 3 (8.8) | 1 (2.9) | ||
Values are presented as number (%).
pCR = pathological complete response; NAC = neoadjuvant chemotherapy; CS = concentric shrinkage; NACI = neoadjuvant chemotherapy with immunotherapy.
Results of the univariate and multivariate analyses of the association with the CS pattern are shown in Table 3. In the univariate analysis, the T stage of the tumor size (p = 0.036) and neoadjuvant therapy regimen (p = 0.002) had a significant association with the CS pattern. Moreover multivariate analysis demonstrated that the neoadjuvant therapy regimen (p = 0.006) had a significant association with the CS pattern.
Table 3. Univariable and multivariable logistics regression analyses of the association with concentric shrinkage.
| Variables | Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|---|
| RR (95% CI) | p-value | RR (95% CI) | p-value | ||
| Age (yr) | 0.221 | 0.182 | |||
| ≤ 50 | Ref. | Ref. | |||
| > 50 | 0.976 (0.938–1.015) | 0.971 (0.930–1.014) | |||
| Tumor size | 0.036 | 0.399 | |||
| T1–T2 | Ref. | Ref. | |||
| T3–T4 | 0.333 (0.120–0.929) | 0.342 (0.028–4.131) | |||
| Lymph node metastases | 0.622 | 0.341 | |||
| Negative | Ref. | Ref. | |||
| Positive | 1.222 (0.550–2.715) | 1.638 (0.592–4.131) | |||
| Nuclear grade | 0.248 | 0.243 | |||
| 1–2 | Ref. | Ref. | |||
| 3 | 1.620 (0.715–3.670) | 1.714 (0.693–4.239) | |||
| Clinical stage* | 0.136 | 0.812 | |||
| II | Ref. | Ref. | |||
| III | 0.471 (0.175–1.267) | 0.733 (0.056–9.519) | |||
| NAC regimen | 0.802 | 0.930 | |||
| Non-anthracycline based | Ref. | Ref. | |||
| Anthracycline based | 1.115 (0.474–2.623) | 1.044 (0.398–0.666) | |||
| Neoadjuvant therapy regimen | 0.002 | 0.006 | |||
| NAC | Ref. | Ref. | |||
| NACI | 0.222 (0.085–0.583) | 0.235 (0.084–0.661) | |||
RR = relative risk; CI = confidence interval; Ref. = reference; NAC = neoadjuvant therapy; NACI = neoadjuvant chemotherapy with immunotherapy.
*Based on the 8th American Joint Committee on Cancer staging system.
The relationship between tumor shrinkage patterns and breast surgery is shown in Table 4. Here, BCS was achieved in 33% of patients with the CS pattern and 28% of those with the NCS pattern. In addition, mastectomy was performed on 67% of patients with the CS pattern and 71% of those with the NCS pattern (p = 0.573).
Table 4. Relationship between tumor shrinkage patterns and breast surgery.
| Parameter | Breast-conserving surgery | Mastectomy | p-value |
|---|---|---|---|
| CS | 14 (33) | 28 (67) | 0.573 |
| NCS | 16 (28) | 41 (71) |
Values are presented as number (%).
CS = concentric shrinkage; NCS = non-concentric shrinkage.
DISCUSSION
To our knowledge, this is the first study to not only to investigate the differences in tumor shrinkage patterns, based on MRI, between NACI and NAC in patients with TNBC but also to investigate the correlation between tumor shrinkage patterns and efficacy. Our results showed that the NACI group was more likely to show a diffuse shrinkage pattern, and the pCR rate was high for all shrinkage patterns.
We observed that the tumor shrinkage patterns associated with NACI were distinct from those associated with NAC. Breast cancers exhibit diverse shrinkage patterns following neoadjuvant therapy. Fukada et al. [17] divided tumor shrinkage patterns into six groups. Previous studies have not shown that NACI and NAC are associated with a different shrinkage pattern model. Our study is the first to find significant differences in tumor shrinkage patterns, based on MRI, with different neoadjuvant regimens for TNBC. The NACI group showed a more diffuse decrease in the shrinkage pattern. Traditional NAC is a treatment method that uses chemicals to prevent cancer cell proliferation, infiltration, and metastasis, and it ultimately kills cancer cells [18,19]. However, the mechanism of action of NACI occurs via the release of a variety of tumor antigens after chemotherapy to induce tumor cell apoptosis. This not only reduces the tumor burden but also eliminates immunosuppressive cells, modulating the immune system’s microenvironment, such that immune cells can be used to recognize and destroy cancer cells [20]. Therefore, different tumor resection mechanisms could lead to bias in different shrinkage patterns.
Consistent with the findings of previous studies, we found that CS is more likely to manifest after NAC and that CS is associated with improved pCR. The T stage of the tumor size was found to be an independent factor affecting the shrinkage pattern. The larger the diameter of the primary tumor, the more likely NCS was to occurred after NAC. CS occurred more frequently after NAC and was associated with pCR. Fukada et al. [17] concluded that CS MRI patterns during NAC were independently associated with breast cancer prognosis. They suggested that these NAC shrinkage patterns might reflect biological characteristics. In patients without CS, residual cells in the NCS pattern could harbor cancer cells that are more resistant to preoperative chemotherapy. Eom et al. [21] proposed that the shrinkage contraction pattern after NAC in patients of TNBC patients is associated with pCR.
NACI resulted in greater pCR for all shrinkage pattern modes in this study. A previous meta-analysis confirmed that patients with TNBC who achieved pCR after neoadjuvant therapy had longer event-free survival and overall survival than patients who did not achieve pCR [22]. The optimal surgical approach for a tumor is influenced by several factors, including anteroposterior tumor size, tumor histology, multifocality, lymphatic invasion, and breast size [23]. BCS is a primary objective of neoadjuvant therapy regimen, where achieving a clear surgical margin is pivotal for successful outcomes. Patients who attain pCR or exhibit unifocal residual disease following NAC have superior rates of four-year ipsilateral breast tumor recurrence-free survival than those with multifocal disease. This distinction can be attributed to the presence of false negative margins during surgery [24]. The 2017 St. Gallen consensus recommends determining the residual tumor size and shrinkage pattern after NAC and reducing the scope of surgery for patients with CS patients accordingly. For patients with CS, the scope of surgery can be appropriately reduced according to the extent of the residual tumor. For patients of NCS, resection should be performed according to the extent of the tumor marked before NAC. Accurate evaluation of the shrinkage pattern and the extent of residual tumors after NAC is essential for selecting the appropriate surgical approach and resection extent, especially for reducing positive surgical margins and the surgical resection rate [25]. However, immunotherapy differs from conventional chemotherapy in that it is associated with different tumor resection mechanisms, and the total pCR rate was higher for all shrinkage patterns. The mechanism of NACI involves the release of multiple tumor antigens following chemotherapy and the subsequent induction of tumor cell apoptosis. Reducing the tumor burden eliminates immunosuppressive cells, thereby permitting immune cells to identify and destroy cancer cells. This transforms a cold tumor into a hot tumor, rendering the tumor vulnerable to internal destruction. BCS can also be considered for patients treated with NCS after NACI and radiologic complete remission based on in preoperative MRI, and a strong desire to undergo BCS. Therefore, there is a need to explore whether the shrinkage patterns of patients after NAC should also be used as a reference to guide the selection of surgical methods after NACI.
The present study had several limitations. First, TNBC is a relatively rare subtype of breast cancer, and thus, the sample size was relatively small. Second, this study was retrospective, and the results need to be verified by performing studies with a larger sample size, with an assessment of shrinkage patterns and long-term survival outcomes.
In summary, our study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC patients treated with NACI.
Footnotes
Funding: This study is supported by grants from National Natural Science Foundation of China (82171898), Deng Feng project of high-level hospital construction (DFJHBF202109), Guangdong Basic and Applied Basic Research Foundation (grant number 2022A1515012277, 2023A1515010222), Guangzhou Science and Technology Project (202002030236), Macao Science and Technology Development Fund (20210701181316106/AKP). Beijing Medical Award Foundation (YXJL-2020-0941-0758), and Beijing Science and Technology Innovation Medical Development Foundation (KC2022-ZZ-0091-5). Funding sources were not involved in the study design, data collection, analysis and interpretation, writing of the report, or decision to submit the article for publication.
Conflict of Interest: The authors declare that they have no competing interests.
Data Availability: The data that support the findings of our study are available from the corresponding author upon reasonable request.
- Conceptualization: Zou J, Wang K.
- Data curation: Zou J, Zhang L, Chen Y, Lin Y, Cheng M, Zheng X, Zhuang X.
- Formal analysis: Zou J, Chen Y, Cheng M.
- Funding acquisition: Wang K.
- Investigation: Zou J.
- Methodology: Zou J.
- Project administration: Zou J, Wang K.
- Resources: Zhang L, Wang K.
- Software: Zou J, Zheng X.
- Supervision: Wang K.
- Validation: Zou J, Zhang L, Wang K.
- Visualization: Wang K.
- Writing - original draft: Zou J.
- Writing - review & editing: Zou J, Zhang L, Lin Y, Cheng M, Zhuang X, Wang K.
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