Abstract
Purpose
Invasive lobular breast cancers (ILCs) respond poorly to neoadjuvant chemotherapy (NAC). The degree of benefit of NAC among non-classic ILC (NC-ILC) variants compared with classic ILCs (C-ILCs) is unknown.
Methods
Consecutive patients with Stage I-III ILC treated from 2003–2019 with NAC and surgery were identified, and grouped as C-ILC or NC-ILC as per the original surgical pathology report, with pathologist (A.G.) review performed if original categorization was unclear. A subset of similarly treated invasive ductal cancers (IDCs) was identified for comparison. Clinicopathologic characteristics and pathologic complete response (pCR) rates were evaluated.
Results
Of 145 patients with ILC, 101 (70%) were C-ILC and 44 (30%) were NC-ILC (IDC cohort: 1157 patients). ILC patients were older, more often cT3/T4 and cN2/N3, and less often high grade compared to IDC patients. Those with NC-ILC were less often ER+/HER2- (55% versus 93%), and more often HER2+ (25% versus 7%) and TN (21% versus 0%, all p<0.001). Breast pCR was more common among NC-ILC, but most frequent in IDC. Nodal pCR rates were also lowest among C-ILC patients, but similar among NC-ILC and IDC patients. On multivariable analysis, C-ILC (OR 0.09) and LVI (OR 0.51) were predictive of lack of breast pCR; non-ER+/HER2- subtypes and breast pCR were predictive of nodal pCR. When our analysis was repeated with patients stratified by receptor subtype, histology was not independently predictive of either breast or nodal pCR.
Conclusion
NC-ILC patients were significantly more likely to achieve breast and nodal pCR compared with C-ILC patients, but when stratified by subtype, histology was not independently predictive of breast or nodal pCR.
Keywords: neoadjuvant chemotherapy, lobular histology, pathologic complete response, breast cancer, non-classic invasive lobular cancers, classic invasive lobular cancers
Introduction
Neoadjuvant chemotherapy (NAC) is increasingly used in the treatment of breast cancer, affording the potential for preoperative tumor shrinkage and nodal disease eradication, which may permit less-extensive surgery. Response to NAC differs by tumor subtype and histology. Specifically, rates of pathologic complete response (pCR) to NAC among patients with invasive lobular carcinoma (ILC) range from 0 to 11%[1–5], and are significantly lower than pCR rates among those with invasive ductal carcinoma (IDC).[6–10]
The observed difference in response may be attributed to the biologic profile of ILC. Lobular carcinoma is a biologically distinct entity commonly characterized by low proliferative rates, hormone receptor positivity, and human epidermal growth factor receptor 2 (HER2) negativity.[11,12] However, ILC itself is a heterogeneous disease, further categorized into classic and non-classic forms. The more common classic ILC (C-ILC) demonstrates a uniquely discohesive growth pattern, with loss of E-cadherin, and a majority of these (≥ 90%) are hormone receptor positive.[11] There are several non-classic ILC (NC-ILC) variants, including the pleomorphic, signet ring, alveolar, histiocytoid and tubulolobular types, which all share the characteristic discohesion, but which have cytologic and architectural features that deviate from classically defined patterns, while also showing lower rates of hormone receptor positivity and higher rates of HER2 positivity than C-ILC.[11] While this difference in biology suggests potential for greater chemosensitivity among non-classic ILC variants, to our knowledge, the response of NC-ILC to NAC in comparison to C-ILC and IDC has not been previously evaluated. In the current era of tailored precision medicine and increasing use of NAC, clarifying the degree of response to chemotherapy in this unique patient population is clinically meaningful.
In this study, we sought to examine rates of pCR in the breast and lymph nodes among classic and non-classic ILC variants in a consecutive population of ILC patients treated with modern NAC, and to compare these to a cohort of patients with IDC similarly treated with NAC.
Materials and Methods
Following Institutional Review Board approval, we identified consecutive female patients with Stage I-III ILC who were treated with NAC followed by surgery at Memorial Sloan Kettering Cancer Center between January 1, 2003 and December 31, 2019. Patients with concurrent metastases at presentation, and those with incomplete records, were excluded.
The original pathology reports of all ILC patients were reviewed for categorization as classic lobular or non-classic lobular, which was uniformly reported in a standardized synoptic format throughout the study period. Non-classic lobular histologies included were defined as the alveolar, mucinous, signet ring, and pleomorphic subtypes. At Memorial Sloan Kettering Cancer Center, cases are exclusively reviewed by pathologists with specific expertise in breast pathology. Immunohistochemical analysis with E-cadherin is performed at the discretion of the reviewing pathologist when confronted with ambiguous histomorphologic features. Cases were re-reviewed by a dedicated breast pathologist (A.G.) if categorization was not definitively provided (n=21). A consecutive subset of pure IDC patients similarly treated with NAC followed by surgery from 2014 to 2019 comprised the comparison cohort. Clinicopathologic characteristics and rates of pCR in the breast and lymph nodes were compared between the C-ILC, NC-ILC, and IDC groups.
Standard clinicopathologic data, neoadjuvant therapy details, and pathologic findings at surgery were collected. Rate of pCR in the breast and lymph nodes, defined as eradication of all invasive carcinoma and ductal carcinoma in situ, were the primary outcomes of interest. Clinicopathologic characteristics were compared between the C-ILC, NC-ILC, and IDC groups using the Wilcoxon rank sum test for continuous variables, and the Chi-square or Fisher’s exact test for categorical variables. Significant variables from the univariate analysis were included in the multivariable logistic regression model examining for associations with breast and nodal pCR. To evaluate the influence of receptor status, this analysis was also performed with patients stratified by subtype, and this method was selected over an interaction analysis to avoid model saturation. The type I error rate was set to 0.05 (α). All analyses were performed using R 3.6.3 (R Core Team, 2020).
Results
From January 2003 to December 2019, 145 patients with ILC received NAC followed by surgery, of whom 101 (69.7%) were C-ILC and 44 (30.3%) were NC-ILC. The comparison IDC cohort included 1157 consecutive patients. Patients with ILC were older (median age in years: 52 C-ILC versus 56 NC-ILC versus 50 IDC), more often cT3/T4 (68.3% C-ILC versus 63.6% NC-ILC versus 28.1% IDC) and cN2/N3 (12.9% C-ILC versus 20.5% NC-ILC versus 7.9% IDC), and less often had high-grade tumors (11.9% C-ILC versus 40.9% NC-ILC versus 70.1% IDC) when compared to those with IDC (all p<0.05) (Table 1). Compared to those with C-ILC, women with NC-ILC cancers were less often estrogen receptor (ER) positive/HER2 negative (93.1% C-ILC versus 54.5% NC-ILC), more frequently progesterone receptor (PR) negative (18.8% C-ILC versus 40.9% NC-ILC), and more often HER2 positive (6.9% C-ILC versus 25.0% NC-ILC) and triple negative (TN) (0% C-ILC versus 20.5% NC-ILC) (p<0.001) (Table 1).
Table 1.
Clinicopathologic characteristics, stratified by cancer histology
| Characteristic | Classic Lobular n = 101 | Non-Classic Lobular n = 44 | Ductal n = 1157 | P |
|---|---|---|---|---|
| Age, years, median (IQR) | 52 (46, 60) | 56 (51, 63) | 50 (42, 59) | 0.002 |
| Clinical T stage 1 2 3 4 |
12 (11.9%) 20 (19.8%) 40 (39.6%) 29 (28.7%) |
2 (4.5%) 14 (31.8%) 18 (40.9%) 10 (22.7%) |
154 (13.3%) 678 (58.6%) 227 (19.6%) 98 (8.5%) |
< 0.001 |
| Clinical N stage 0 1 2 3 |
35 (34.7%) 53 (52.5%) 7 (6.9%) 6 (5.9%) |
11 (25.0%) 24 (54.5%) 6 (13.6%) 3 (6.8%) |
345 (29.8%) 721 (62.3%) 46 (4.0%) 45 (3.9%) |
0.02 |
| Biopsy-proven node positive | 36 (35.6%) | 24 (54.5%) | 702 (60.7%) | < 0.001 |
| Receptor status ER+/HER2- ER+/HER2+ ER-/HER2+ ER-/HER2- |
94 (93.1%) 7 (6.9%) 0 (0%) 0 (0%) |
24 (54.5%) 8 (18.2%) 3 (6.8%) 9 (20.5%) |
362 (31.3%) 283 (24.5%) 181 (15.6%) 331 (28.6%) |
< 0.001 |
| Lymphovascular invasion Yes No Unknown |
41 (40.6%) 60 (59.4%) 0 (0%) |
16 (36.4%) 28 (63.6%) 0 (0%) |
350 (30.3%) 617 (53.3%) 190 (16.4%) |
0.68 |
| Grade Low Intermediate High Unknown |
5 (5.0%) 63 (62.4%) 12 (11.9%) 21 (20.8%) |
0 (0%) 15 (34.1%) 18 (40.9%) 11 (25.0%) |
7 (0.6%) 320 (27.7%) 811 (70.1%) 19 (1.6%) |
< 0.001 |
| Breast surgery Lumpectomy Mastectomy |
9 (8.9%) 92 (91.1%) |
10 (22.7%) 34 (77.3%) |
518 (44.8%) 639 (55.2%) |
< 0.001 |
| Axillary surgery SLNB only SLNB + ALND ALND only |
16 (15.8%) 26 (25.7%) 59 (58.4%) |
7 (15.9%) 10 (22.7%) 27 (61.4%) |
673 (58.2%) 305 (26.4%) 179 (15.5%) |
< 0.001 |
Unknown among n = 190 patients (all ductal cancer patients)
Abbreviations: IQR, interquartile range; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; SLNB, sentinel lymph node biopsy; ALND, axillary lymph node dissection
Prior to surgery, 95% of all ILC and IDC patients received an AC-based chemotherapy regimen, and all HER2 positive patients received single- or dual-agent HER2 targeted therapy. Mastectomy was performed in 92 (91.1%) of C-ILC patients versus 34 (77.3%) of NC-ILC patients (p<0.001). Axillary lymph node dissection (ALND) was performed in 84% of both C-ILC and NC-ILC patients. In comparison, mastectomy was performed in 55%, and ALND performed in 42% of IDC patients, respectively (Table 1).
Pathologic findings at surgery are summarized in Table 2. Residual tumor size was similar between ILC types (median size: 2.7 cm C-ILC versus 2.8 cm NC-ILC), but higher than that seen among IDC patients (median size: 0.45 cm, p<0.001). The rate of breast pCR was lowest among those with C-ILC (1%), higher among those with NC-ILC (16%), and highest among those with IDC (30.1%, p<0.001). As per standard definitions, the finding of lobular carcinoma in situ (LCIS) alone on final pathology would have been considered a breast pCR; however, this did not occur in any patients in this study. Rates of nodal pCR were lowest among C-ILC patients, but similar among NC-ILC and IDC patients. Nodal pCR was evaluated both among those who were preoperatively clinically node positive (nodal pCR rate 9.1% C-ILC versus 36.4% NC-ILC versus 46.4% IDC, p<0.001), and among those who were preoperatively biopsy-proven node positive (nodal pCR rate 2.8% C-ILC versus 45.8% NC-ILC versus 42.6% IDC, p<0.001) (Table 2).
TABLE 2.
Pathologic findings, stratified by cancer histology
| Characteristic | Classic Lobular n = 101 | Non-Classic Lobular n = 44 | Ductal n = 1157 | P |
|---|---|---|---|---|
| Breast | ||||
| Residual tumor size, median (range), cm | 2.7 (0, 13.5) | 2.8 (0, 12) | 0.45 (0, 18) | < 0.001 |
| ypT stage 0 is 1 2 3 |
1 (1.0%) 0 (0%) 27 (26.7%) 46 (45.5%) 27 (26.7%) |
7 (15.9%) 0 (0%) 10 (22.7%) 18 (40.9%) 9 (20.5%) |
348 (30.1%) 98 (8.5%) 491 (42.4%) 179 (15.5%) 41 (3.5%) |
< 0.001 |
| Breast pCR (ypT0) | 1 (1.0%) | 7 (15.9%) | 348 (30.1%) | < 0.001 |
| Lymph nodes | ||||
| # positive lymph nodes, median (range) | 4 (0, 38) | 2 (0, 28) | 0 (0, 49) | < 0.001 |
| # excised lymph nodes, median (range) | 15 (1, 66) | 16 (1, 33) | 6 (1, 54) | < 0.001 |
| ypN stage 0 1 2 3 |
22 (21.8%) 25 (24.8%) 27 (26.7%) 27 (26.7%) |
17 (38.6%) 7 (15.9%) 6 (13.6%) 14 (31.8%) |
688 (59.5%) 306 (26.4%) 116 (10.0%) 47 (4.1%) |
< 0.001 |
| Nodal pCR among cN+ by exam | 6 / 66 (9.1%) | 12 / 33 (36.4%) | 377 / 812 (46.4%) | < 0.001 |
| Nodal pCR among biopsy-proven cN+ | 1 / 36 (2.8%) | 11 / 24 (45.8%) | 299 / 702 (42.6%) | < 0.001 |
Abbreviations: pCR, pathologic complete response; cN+, clinically node positive
Associations with breast and nodal pCR were examined using logistic regression models and are summarized in Table 3. Classic lobular histology (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.01–0.46, p=0.02) and presence of lymphovascular invasion (OR 0.51, 95% CI 0.35–0.75, p<0.001) were associated with a low likelihood of breast pCR, while non-ER positive/HER2 negative subtypes were associated with higher likelihood. Non-classic lobular histology (OR 4.25, 95% CI 1.33–12.9, p=0.01), achievement of breast pCR (OR 14.6, 95% CI 6.84–33.7, p<0.001), and non-ER positive/HER2 negative subtypes were predictive of nodal pCR (Table 3). However, when the analysis was repeated with patients stratified by receptor subtype, tumor histology was not independently associated with either breast pCR or nodal pCR.
TABLE 3.
Multivariable regression analyses of risk factors for achievement of breast pCR and nodal pCR
| Characteristic | Odds Ratio | 95% Confidence Interval | P |
|---|---|---|---|
| Breast pCR | |||
| Clinical T stage 1 2 3 4 |
(ref) 0.87 0.56 1.04 |
– 0.54–1.40 0.31–0.99 0.51–2.09 |
– 0.6 0.05 > 0.9 |
| Histology Invasive ductal Classic lobular Non-classic lobular |
(ref) 0.09 0.98 |
– 0.01–0.46 0.36–2.37 |
– 0.02 > 0.9 |
| Receptor status ER+/HER2- ER+/HER2+ ER-/HER2+ ER-/HER2- |
(ref) 3.43 14.5 3.20 |
– 2.09–5.74 8.49–25.5 1.96–5.36 |
– < 0.001 < 0.001 < 0.001 |
| Lymphovascular invasion No Yes |
– 0.51 |
– 0.35–0.75 |
– < 0.001 |
| Nodal pCR | |||
| Clinical N stage 0 1 2 3 |
(ref) 0.09 0.13 0.10 |
– 0.04–0.18 0.04–0.43 0.03–0.29 |
– < 0.001 0.001 < 0.001 |
| Histology Invasive ductal Classic lobular Non-classic lobular |
(ref) 0.80 4.25 |
– 0.27–2.33 1.33–12.9 |
– 0.7 0.01 |
| Receptor status ER+/HER2- ER+/HER2+ ER-/HER2+ ER-/HER2- |
(ref) 2.79 5.42 1.89 |
– 1.49–5.33 2.19–14.0 1.02–3.50 |
– 0.002 < 0.001 0.04 |
| Achievement of breast pCR (ypT0) | 14.6 | 6.84–33.7 | < 0.001 |
Abbreviations: pCR, pathologic complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2
Discussion
This study provides evidence, in a consecutive cohort of lobular breast cancer patients treated with NAC followed by surgery over a 16-year period, that those with NC-ILC more frequently demonstrated pCR in the breast and nodes compared to those with C-ILC, and had a nodal pCR rate similar to that seen in IDC. This improved chemosensitivity was likely a result of the biologic profile of NC-ILC, with a greater proportion of PR negative (41%), HER2 positive (25%), TN (21%), and high-grade (41%) tumors than seen with C-ILC.
Multiple early studies have demonstrated a poor response of lobular carcinomas to NAC, with overall pCR rates reported to range from 0 to 11% among ILC patients, as compared to 9% to 25% among IDC patients.[2,4,5,7–10,13,14] This may account for the small but statistically significant decrease in the utilization of NAC for ILC patients from 4.7% to 4.2% (p=0.007) observed in a study from the National Cancer Database (NCDB) that included 69,312 ILC patients treated between 2010 and 2016.[15] However, past studies have not compared the differential benefit between NC-ILC and C-ILC variants. To our knowledge, this is the first study examining patterns of response of NC-ILC to NAC. In the present era of individually tailored breast cancer treatment, evaluating the response of NC-ILC variants to chemotherapy is necessary to refine the optimal treatment choices for this unique patient population.
Intrinsic tumor biology and the resultant efficacy of modern targeted chemotherapy is likely the fundamental determinant of tumor response, rather than morphology alone. A large body of evidence has established the TN and HER2 positive subtypes as being the most chemo-sensitive subsets of breast cancer, although few studies have examined this among pure ILC populations. Lips et al. compared patients with 676 IDCs and 75 ILCs in 2 prospective trials of NAC in which receptor status, grade, and p53 expression were predictive of overall pCR, and accounted for the difference in response between the lobular and ductal carcinomas.[4] Similarly, in a study of 1895 ER positive patients with Stage I–III breast cancer who received NAC from 1990 to 2010, pCR rate did not differ by histology after adjusting for differences in grade.[7] In a study from the NCDB including 384,887 women who received NAC, only 8.7% of ILC patients achieved pCR as compared to 23.2% of IDC patients, but response was improved among ILC patients who were HER2 positive or TN.[10] Among populations of only ER positive/HER2 negative patients treated with NAC, greater chemotherapy benefit has also been observed among those lacking PR expression. In a cohort of 211 ER positive/HER2 negative patients treated with NAC, Lips et al. reported a 35% rate of breast pCR among PR negative tumors as compared to 12% among PR positive tumors (p<0.001).[16] Similarly, Petruolo et al. found the highest rates of nodal pCR among PR negative and high-grade tumors in a population of 402 ER positive/HER2 negative cancers treated with NAC between 2007 and 2016.[17] The principle that tumor biology, of which receptor status is a critical determinant, is a key factor in response to chemotherapy, is confirmed in our study, with a higher frequency of breast and nodal pCR seen among the more frequently PR negative, HER2 positive, and TN NC-ILC variants.
Tumor downstaging with NAC may offer surgical benefit by permitting some patients to undergo less-extensive surgery in both the breast and axilla. While the current study was not designed to examine rates of surgical downstaging, it was observed that rates of mastectomy were highest among C-ILC and lowest among IDC patients (91% C-ILC versus 77% NC-ILC versus 55% IDC, p<0.001), corresponding to rates of breast pCR (1% C-ILC versus 16% NC-ILC versus 30% IDC). Nodal pCR rates were significantly higher among NC-ILC patients than C-ILC patients, and were similar to those seen in IDC patients. While most previous studies suggest poor rates of downstaging among ILC patients[7–9,13,17,18], the NC-ILC variants have not been evaluated separately. Boughey et al. found no increase in rates of breast-conserving surgery (BCS) among ILC patients receiving NAC in a study of pure ILC patients treated between 1998 and 2006.[18] Similarly, tumor downstaging and rates of BCS were significantly lower among those with ILC in a study comparing 177 ILC ER positive patients to 1718 IDC ER positive patients, and lobular histology was independently predictive of mastectomy.[7] In a modern series of 402 ER positive/HER2 negative patients treated with NAC from 2007 to 2016, ILC patients were less likely than IDC patients to downstage in the breast or axilla, but the highest rates of BCS eligibility were seen among PR negative and poorly differentiated tumors[17], again emphasizing the influence of tumor biology on response to NAC. The moderately higher rate of breast pCR and dramatically higher rate of nodal pCR among NC-ILC patients as compared to C-ILC patients in our study suggests that this more biologically aggressive subset of lobular cancers may derive a comparatively greater surgical benefit from NAC.
Given the frequently ER rich nature of ILC and overall poor response to NAC, there has been mounting interest in the use of neoadjuvant endocrine therapy (NET) for ILC. In a study of 61 postmenopausal women with locally advanced ER positive ILC who received neoadjuvant letrozole for at least 3 months, while no pCRs were observed, there was a mean reduction in tumor volume by 66%, with an 81% rate of BCS among 31 patients who had undergone surgery by the time of publication.[19] In a more recent study by Montagna et al. of consecutive Stage I–III hormone receptor positive/HER2 negative breast cancer patients treated with NET (n=127) or NAC (n=338) between 2009 and 2019, 77% of BCS ineligible patients successfully downstaged to BCS eligible. Nodal pCR was more frequent than breast pCR with NET (11% versus 1.6%), but nodal downstaging rates with NET and NAC were similar. Surprisingly, no lobular cancer patients who received NET achieved a nodal pCR, as compared to 14% of such patients treated with NAC.[20] This is similar to a study from the NCDB of 5942 ER positive, node-positive pure ILC patients in which no patients who received NET experienced pCR, compared to 2.5% of those who received NAC (p<0.001).[14] While there has been an increase in the use of NET for ILC in recent years[15], uncertainty remains regarding optimal treatment regimen, duration, and patient selection, which a number of ongoing randomized trials aim to address in the future. Furthermore, genomic testing is now routinely employed among early-stage hormone receptor positive/HER2 negative patients with and without nodal metastasis to identify candidates for chemotherapy. The Oncotype DX Breast Recurrence Score (Exact Sciences, Redwood City, CA) is known to be correlated to various clinicopathologic features, including high grade and low PR expression, and higher recurrence scores are likely among the more frequently high-grade and PR negative NC-ILC group. Such adjuncts may become increasingly useful in determining which lobular breast cancers will derive the greatest benefit from chemotherapy.
Limitations of our study include its retrospective and single-institution nature, with a small cohort of 145 lobular cancer patients with even smaller subsets of classic and non-classic ILC, and a time period largely preceding the routine use of genomic testing in practice. Additionally, patients treated in the early years did not receive modern systemic therapies. It is also possible that with larger cohorts of patients, a greater impact of histology may have been elucidated. However, this is the first study that, to our knowledge, examines the differential benefit of NAC for non-classic variants of lobular cancer and affirms the crucial role of tumor biology in determining response to chemotherapy. The greater likelihood of NC-ILC tumors being PR negative, HER2 positive, TN, and high grade likely accounts for the improved rates of nodal and breast pCR as compared to C-ILC tumors, which may afford a meaningful surgical benefit for appropriately selected patients. Consideration of all tumor features, and a nuanced and individually tailored approach is of paramount importance when considering a patient for neoadjuvant therapy.
Conclusion
In this consecutive population of lobular breast cancer patients treated with NAC and surgery over a 16-year period, those with NC-ILC more often achieved pCR in both the breast and lymph nodes as compared to C-ILC, and nodal pCR rates were similar to those seen in IDC. This improved chemosensitivity was a consequence of the more frequently PR negative, HER2 positive, TN, and high-grade biologic profile of NC-ILC. The use of NAC for appropriately selected patients may afford a meaningful surgical benefit.
Synopsis:
In comparing neoadjuvant chemotherapy benefit between non-classic and classic invasive lobular carcinomas (ILCs), non-classic ILC patients were more often HER2+, triple-negative, or PR-, and more likely to achieve pathologic complete response (pCR) in the breast and lymph nodes.
Acknowledgments and Funding Information:
The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center, and this study was presented in poster format at the Society of Surgical Oncology 2021 International Conference on Surgical Cancer Care, March 18–19, 2021. Dr. Anne Grabenstetter is a consultant for Paige.AI, and all other authors have no conflicts of interest or commercial interests to disclose. This study was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board.
Footnotes
Statements & Declarations
Competing Interests: Dr. Anne Grabenstetter is a consultant for Paige.AI. All other authors have no conflict of interest or commercial interests to disclose.
Ethics Approval: This study was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board.
Consent to Participate: Not applicable
Consent to Publish: Not applicable
Data Availability:
The datasets generated during and/or analyzed during the current study are not shareable based on Memorial Sloan Kettering Cancer Center institutional policy.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are not shareable based on Memorial Sloan Kettering Cancer Center institutional policy.