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The Impact of Chemotherapy Prescription on Long-Term Survival Outcomes in Early-Stage Invasive Lobular Carcinoma – A Systematic Review and Meta-Analysis

  • Matthew G. Davey
    Correspondence
    Corresponding author: Dr. Matthew G. Davey, Department of Surgery, National University of Ireland Galway H91YR71, Republic of Ireland. Tel.: +35391524411
    Affiliations
    Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway H91 YR71, Republic of Ireland
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  • Stephen Keelan
    Affiliations
    Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway H91 YR71, Republic of Ireland
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  • Aoife J. Lowery
    Affiliations
    Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway H91 YR71, Republic of Ireland
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  • Michael J. Kerin
    Affiliations
    Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Galway H91 YR71, Republic of Ireland
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Open AccessPublished:September 19, 2022DOI:https://doi.org/10.1016/j.clbc.2022.09.005

      Abstract

      Introduction

      Invasive lobular carcinoma (ILCs) are typically endocrine responsive breast cancers which respond poorly to chemotherapy. The long-term survival advantage of prescribing chemotherapy in such cases remains unclear.

      Aims

      To perform a systematic review and meta-analysis assessing the impact of prescribing chemotherapy in such patients on long-term disease-free (DFS) and overall (OS) survival outcomes.

      Methods

      A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. 10-year DFS and OS were pooled as odds ratios (ORs) with 95% confidence intervals (CI) using the Mantel-Haenszel method. Time-to-effect modelling was performed using the generic inverse variance method.

      Results

      Overall, 9 studies including 28,218 patients were included. The mean follow-up was 74 months (range: 0 – 150 months) and mean age was 60 years (range: 22 – 90 years). Of these, 34.7% received chemotherapy (9,797/28,218) and 66.3% did not receive chemotherapy (18,421/28,218). Chemotherapy prescription failed to improve 10-year DFS (OR: 0.89, 95% CI: 0.65 – 1.23) and OS (OR: 0.92, 95% CI: 0.72 – 1.18). When using time-to-effect modelling, chemotherapy prescription failed to improve DFS (hazard ratio (HR): 1.01, 95% CI: 0.78 – 1.31) and OS (HR: 1.07, 95% CI: 0.89 – 1.27, I2= 67%).

      Conclusion

      This meta-analysis illustrates no long-term survival advantage associated with chemotherapy prescription in the setting of early-stage ILC. In the absence of well-designed, prospective clinical trials evaluating the impact of chemotherapy on long-term outcomes in ILC, these results should be considered by the multidisciplinary team when deciding on the value of systemic chemotherapy prescription in ILC.

      PROSPERO Registration

      CRD42022327137

      Keywords

      Introduction

      Invasive lobular carcinoma (ILC) represents the second most common breast cancer histological subtype and accounts for 5-15% of diagnoses globally
      • Wilson N.
      • et al.
      Lobular Breast Cancer: A Review.
      ,
      • Thomas M.
      • et al.
      Invasive lobular breast cancer: A review of pathogenesis, diagnosis, management, and future directions of early stage disease.
      . Despite representing a minority share of all breast tumours, ILC contributes a similar share to the global cancer burden as ovarian carcinoma, central nervous system tumours, and malignant melanoma
      • Sung H.
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
      . Notwithstanding, ILCs remain an understudied breast cancer histological subtype
      • Mouabbi J.A.
      • et al.
      Invasive lobular carcinoma: an understudied emergent subtype of breast cancer.
      ,
      • Luveta J.
      • et al.
      Invasive Lobular Breast Cancer as a Distinct Disease: Implications for Therapeutic Strategy.
      , particularly as these tumours possess unique biological characteristics and illustrate a different natural history to the more common IDC subtype. ILCs have the tendency to develop in older patients, who typically have more advanced disease
      • Wilson N.
      • et al.
      Lobular Breast Cancer: A Review.
      ,
      • Zengel B.
      • et al.
      Comparison of the clinicopathological features of invasive ductal, invasive lobular, and mixed (invasive ductal + invasive lobular) carcinoma of the breast.
      , and these cancers exhibit peculiar metastatic patterns once relapse occurs
      • Korhonen T.
      • et al.
      The impact of lobular and ductal breast cancer histology on the metastatic behavior and long term survival of breast cancer patients.
      . Furthermore, ILCs are typically indolent (moderate-to-well differentiated) tumours with the propensity to develop strong estrogen and/or progesterone receptor positivity and human epidermal growth factor receptor-2 negativity (ER+/PgR+/HER2-)
      • Luveta J.
      • et al.
      Invasive Lobular Breast Cancer as a Distinct Disease: Implications for Therapeutic Strategy.
      . Accordingly, ILCs tend to be endocrine responsive
      • Rakha E.A.
      • et al.
      Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes.
      , chemoinsensitive cancers
      • O'Connor D.J.
      • et al.
      Differences in sensitivity to neoadjuvant chemotherapy among invasive lobular and ductal carcinoma of the breast and implications on surgery-A systematic review and meta-analysis.
      , with surgery combined with multimodal therapeutics proving curative for the majority
      • Wilson N.
      • et al.
      Lobular Breast Cancer: A Review.
      ,
      • Cocco D.
      • et al.
      Invasive Lobular Breast Cancer: Data to Support Surgical Decision Making.
      ,
      • Sharma S.D.
      • et al.
      Surgical management of lobular carcinoma from a national screening program: a retrospective analysis.
      .
      ILC represent a unique histological subtype
      • Chen Z.
      • et al.
      Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma.
      . These cancers are characterized by small, non-cohesive epithelial cells which are dispersed individually in a single-file linear pattern in a fibrous stroma of the breast parenchyma, with loss of expression of E-cadherin (CDH1) cell adhesion molecule occurring in 60-90%
      • Ciriello G.
      • et al.
      Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.
      • Christgen M.
      • et al.
      E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements.
      • Teo K.
      • et al.
      E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer.
      . Loss of CDH1 expression is a renowned cellular hallmark of ILC, with histopathological measurement of the biomarker recommended within expert statements for breast carcinoma workup
      • De Schepper M.
      • et al.
      Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer.
      . Given these unique histological parameters, it is imperative that the multidisciplinary team consider an array of host, tumour, and therapeutic factors when treating patients with ILC disease, for example the propensity for strong responsiveness to endocrine agents combined with reported modest sensitivity to systemic chemotherapy, when compared to patients with other histological subtypes
      • O'Connor D.J.
      • et al.
      Differences in sensitivity to neoadjuvant chemotherapy among invasive lobular and ductal carcinoma of the breast and implications on surgery-A systematic review and meta-analysis.
      . Despite these differences, there are currently no expert consensus statements or guidelines which focus on optimising systemic therapy specific to lobular histology
      • Jacobs C.
      • et al.
      Treatment choices for patients with invasive lobular breast cancer: a doctor survey.
      . This often leads to breast cancers being treated en masse with systemic chemoendocrine therapies with limited consideration for histological subtype
      • Kalinsky K.
      • et al.
      21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.
      ,
      • Sparano J.A.
      • et al.
      Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
      . Thus, the perceived benefit of prescribing systemic chemotherapy in the setting of early-stage ILC may be brought into question or may not be completely understood.
      At the time of writing, there are no prospective, randomised clinical trials evaluating the impact of chemotherapy prescription on long-term survival outcomes in patients who are being treated with curative intent for early-stage ILC. Accordingly, the aim of the current study was to perform a systematic review and meta-analysis assessing the impact of prescribing chemotherapy in such patients on long-term survival outcomes.

      Methods

      Materials and Methods

      A systematic review was performed in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist and meta-analysis and systematic reviews of observational studies (MOOSE) guidelines
      • Moher D.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ,
      • Stroup D.F.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      . This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022327137). Local institutional ethical approval was not required for this study.

      Search Strategy

      An electronic search was performed of the PubMed, Embase, and Cochrane databases on the 3rd March 2022 for relevant studies suitable for inclusion in this study. The search was performed of all fields under the following headings: ((carcinoma, lobular[MeSH Terms]) AND (chemotherapies[MeSH Terms])) AND (breast cancer[MeSH Terms]), which were linked with the Boolean operator ‘AND’. Included studies were limited to those published in the English language and to studies with full-text articles available. Included studies were not restricted based on the year of publication. Initially, all titles were screened, and studies deemed appropriate had their abstracts and full texts reviewed.

      Inclusion and Exclusion Criteria

      Studies meeting the following inclusion criteria were included: (1) Studies assessing the impact of chemotherapy on long-term survival outcomes (i.e.: hazard ratios (HR), 10-year disease-free (DFS) and/or overall (OS) survival) for patients diagnosed with early-stage ILC; (2) eligible studies had to provide full-text manuscripts. Studies meeting any of the following exclusion criteria were excluded from this study: (1) Studies not evaluating the impact of chemotherapy on long-term survival outcomes for patients diagnosed with early-stage ILC; (2) studies reporting outcomes solely in relation to ILC subgroups (e.g.: pleomorphic ILC); (3) conference abstracts; (4) review articles; (5) studies including less than 100 patients in their series; (6) case reports, or (7) editorial articles.

      Data Extraction and Quality Assessment

      Two independent reviewers performed the literature search using a predesigned search strategy. Duplicate studies were manually removed. Each reviewer then reviewed the titles, abstracts and/or full texts of the retrieved manuscripts to ensure all inclusion criteria were met, before extracting the following data: (1) first author name; (2) year of publication; (3) study design; (4) country of origin; (5) number of patients diagnosed with ILC included; (6) number of patients undergoing chemotherapy; (7) number of patients not undergoing chemotherapy; (8) basic clinicopathological data (e.g.: age at diagnosis, tumour staging; follow-up, etc.); and (11) long-term DFS and OS outcomes from each study. Methodological and risk of bias assessment of the included studies was undertaken using the Newcastle Ottawa Risk of Bias Assessment tool for observational studies
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      .

      Definitions

      Disease-free survival – freedom from invasive disease recurrence or death.
      Overall survival – freedom from death due to any cause.

      Statistical Analysis

      Fisher's Exact (†) test was used as appropriate to determine the association between chemotherapy prescription and long-term survival
      • Kim H.Y.
      Statistical notes for clinical researchers: Chi-squared test and Fisher's exact test.
      . Thereafter, survival outcomes were expressed as dichotomous or binary outcomes, reported as odds ratios (OR) and 95% confidence intervals (95% CI) following estimation using the Mantel-Haenszel method. Data specific to patient outcomes and chemotherapy prescription (expressed as HR, 95% confidence intervals (95% CI) and P-values) were directly extracted from tables and study text. HR and associated standard errors were calculated from Kaplan-Meier curves where relevant. Time-to-effect modelling was then performed using the generic inverse variance method. Either fixed or random-effects modelling were applied on the basis of whether significant heterogeneity (I2 >50%) existed between studies included in the analysis. Symmetry funnel plots were used to assess publication bias. Statistical heterogeneity was determined using I2 statistics. All tests of significance were two-tailed with P<0.050 indicating statistical significance. Descriptive statistics were performed using the Statistical Package for Social Sciences (SPSS) version 26 (International Business Machines Corporation, Armonk, New York). Meta-analysis was performed using Review Manager (RevMan), Version 5.4 (Nordic Cochrane Centre, Copenhagen, Denmark).

      RESULTS

      Literature search

      The systematic search strategy identified a total of 853 studies, of which 7 duplicate studies were manually removed. The remaining 846 studies had their titles screened for relevance before 30 abstracts and 17 full texts were reviewed for edibility. In total, 9 studies fulfilled the inclusion criteria and were included in this systematic review
      • Chen X.H.
      • et al.
      21-gene recurrence score and adjuvant chemotherapy decisions in patients with invasive lobular breast cancer.
      • de Nonneville A.
      • et al.
      Adjuvant chemotherapy in lobular carcinoma of the breast: a clinicopathological score identifies high-risk patient with survival benefit.
      • Hu G.
      • et al.
      Adjuvant chemotherapy could not bring survival benefit to HR-positive, HER2-negative, pT1b-c/N0–1/M0 invasive lobular carcinoma of the breast: a propensity score matching study based on SEER database.
      • Iorfida M.
      • et al.
      Invasive lobular breast cancer: subtypes and outcome.
      • Jenkins J.A.
      • et al.
      The 70-gene signature test as a prognostic and predictive biomarker in patients with invasive lobular breast cancer.
      • Marmor S.
      • et al.
      Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast.
      • Metzger-Filho O.
      • et al.
      Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.
      • Watanuki R.
      • et al.
      Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.
      • Truin W.
      • et al.
      Effect of adjuvant chemotherapy in postmenopausal patients with invasive ductal versus lobular breast cancer.
      (Figure 1).
      Figure 1
      Figure 1PRISMA flowchart illustrating the systematic search process.

      Study Characteristics

      Of the 9 included studies, 44.4% provided data from the United States
      • Hu G.
      • et al.
      Adjuvant chemotherapy could not bring survival benefit to HR-positive, HER2-negative, pT1b-c/N0–1/M0 invasive lobular carcinoma of the breast: a propensity score matching study based on SEER database.
      ,
      • Jenkins J.A.
      • et al.
      The 70-gene signature test as a prognostic and predictive biomarker in patients with invasive lobular breast cancer.
      ,
      • Marmor S.
      • et al.
      Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast.
      ,
      • Watanuki R.
      • et al.
      Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.
      and European
      • de Nonneville A.
      • et al.
      Adjuvant chemotherapy in lobular carcinoma of the breast: a clinicopathological score identifies high-risk patient with survival benefit.
      ,
      • Iorfida M.
      • et al.
      Invasive lobular breast cancer: subtypes and outcome.
      ,
      • Metzger-Filho O.
      • et al.
      Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.
      ,
      • Truin W.
      • et al.
      Effect of adjuvant chemotherapy in postmenopausal patients with invasive ductal versus lobular breast cancer.
      translational research facilities respectively (both 4/9). All included studies were of retrospective design (100.0%, 9/9). Publication dates of included studies ranged from 2012 – 2022. Basic study data from the included 9 studies are outlined in Table 1. Risk of bias performed using the Newcastle-Ottawa Scale are outlined in detail in the supplementary material (S1).
      Table 1Details of the 9 included studies in this analysis.
      AuthorYearStudyCountryNumberNumber ChemoNumber ControlMean age in years (Range)Follow-up in months (Range)NOS
      Chen2018ChinaRC64671246522160 (22-90)63 (0-143)5
      de Nonneville2019FranceRC23088231485-585
      Hu2020USARC357017851785--6
      Iorfida2012ItalyRC981345636-89 (0-150)5
      Jenkins2022USARC25614592102-405
      Marmor2017USARC409513472748--7
      Metzger-Filho2019PortugalRC33717016755(48-64)956
      Truin2012NLRC368515152170-677
      Watanuki2020USARC421421072107601297
      Chemo; chemotherapy, NL; Netherlands, RC; retrospective cohort, USA; United States of America, NOS; Newcastle Ottawa Scale

      Clinicopathological Characteristics

      Overall, 28,218 patients were included in the 9 included studies. Of these, 34.7% received chemotherapy (9,797/28,218) and 66.3% did not receive chemotherapy (18,421/28,218). Seven studies reported follow-up data
      • Chen X.H.
      • et al.
      21-gene recurrence score and adjuvant chemotherapy decisions in patients with invasive lobular breast cancer.
      ,
      • de Nonneville A.
      • et al.
      Adjuvant chemotherapy in lobular carcinoma of the breast: a clinicopathological score identifies high-risk patient with survival benefit.
      ,
      • Iorfida M.
      • et al.
      Invasive lobular breast cancer: subtypes and outcome.
      ,
      • Jenkins J.A.
      • et al.
      The 70-gene signature test as a prognostic and predictive biomarker in patients with invasive lobular breast cancer.
      ,
      • Metzger-Filho O.
      • et al.
      Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.
      • Watanuki R.
      • et al.
      Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.
      • Truin W.
      • et al.
      Effect of adjuvant chemotherapy in postmenopausal patients with invasive ductal versus lobular breast cancer.
      and the mean follow-up was 74 months (range: 0 – 150 months). Three studies reported patient age
      • Chen X.H.
      • et al.
      21-gene recurrence score and adjuvant chemotherapy decisions in patients with invasive lobular breast cancer.
      ,
      • Metzger-Filho O.
      • et al.
      Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.
      ,
      • Watanuki R.
      • et al.
      Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.
      and the mean age of included patients was 60 years (range: 22 – 90 years) (Table 2).
      Table 2Clinicopathological data of the 9 included studies in this analysis.
      AuthorYearTumour StagingNodal StatusSubtypesChemotherapyControl
      Chen2018T1-T2N0 or N1ER+/HER2-aCT + aHTaHT
      de Nonneville2019T1-T2N0 or N1ER+/HER2-aCT + aHTaHT
      Hu2020T1N0 or N1ER+/HER2-aCT + aHTaHT
      Iorfida2012T1-3N1-3All subtypesaCTaHT or none
      Jenkins2022T1-3N- or N+ER+aCTNone
      Marmor2017Stage I-IIN0 or N1ER+/HER2-aCT + aHTaHT
      Metzger-Filho2019T1-3N- or N+ER+aCT-
      Truin2012T1-T4N0 or N1ER+aCT + aHTaHT
      Watanuki2020T1-T4N0-N3All subtypesNAC or aCTNET or aHT
      T; tumour stage, N; nodal stage/status, ER+; estrogen receptor positive, HER2-; human epidermal growth factor receptor-2 negative, aCT; adjuvant chemotherapy, aHT; adjuvant hormonal therapy, NAC; neoadjuvant chemotherapy, NET; neoadjuvant endocrine therapy

      Impact of Chemotherapy on Disease-Free Survival

      At 10-years follow-up, a higher proportion of patients who had received chemotherapy remained free of disease recurrence or death (83.4% - 2,444/2,930 vs. 80.3%, 2,883/3,592 P=0.001, †). At meta-analysis, 10-year DFS was similar for those who received chemotherapy versus those who did not receive chemotherapy (OR: 0.89, 95% CI: 0.65 – 1.23, I2= 83%) (Figure 2.A). Similarly, DFS was similar for those who received chemotherapy versus those who did not receive chemotherapy when using time-to-effect modelling (HR: 1.01, 95% CI: 0.78 – 1.31, I2= 73%) (Figure 2.B).
      Figure 2
      Figure 2Forest plots illustrating the impact of chemotherapy prescription on disease-free survival at (A) 10-years post treatment and (B) using time-to-effect modelling in patients previously treated with curative intent for early-stage invasive lobular carcinoma.

      Impact of Chemotherapy on Overall Survival

      At 10-years follow-up, a similar proportion of patients who had received chemotherapy were still alive compared to those who did receive chemotherapy (76.3% - 4,421/5,792 vs. 75.9% 6,459/8,510, P=0.563, †). At meta-analysis, 10-year OS was similar for those who received chemotherapy versus those who did not receive chemotherapy (OR: 0.92, 95% CI: 0.72 – 1.18, I2= 89%) (Figure 3.A). Similarly, OS was similar for those who received chemotherapy versus those who did not receive chemotherapy when using time-to-effect modelling (HR: 1.07, 95% CI: 0.89 – 1.27, I2= 67%) (Figure 3.B).
      Figure 3
      Figure 3Forest plots illustrating the impact of chemotherapy prescription on overall survival at (A) 10-years post treatment and (B) using time-to-effect modelling in patients previously treated with curative intent for early-stage invasive lobular carcinoma.

      Discussion

      The most important finding in this meta-analysis is the data illustrating that there is no survival advantage associated with prescribing systemic chemotherapies in the setting of localised ILC. These results are of the utmost importance within the current breast cancer management paradigm, as there is currently a paucity of expert consensus statements or guidelines providing recommendations for optimising systemic chemotherapy use in ILC. Several translational and clinical research studies have illustrated the chemoinsensitive nature of ‘pure’ ILC
      • Wilson N.
      • et al.
      Lobular Breast Cancer: A Review.
      ,
      • O'Connor D.J.
      • et al.
      Differences in sensitivity to neoadjuvant chemotherapy among invasive lobular and ductal carcinoma of the breast and implications on surgery-A systematic review and meta-analysis.
      ,
      • Cristofanilli M.
      • et al.
      Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes.
      . Although improved oncological outcomes are typically observed in patients who respond favourably to chemotherapy
      • Davey M.G.
      • et al.
      Clinicopathological response to neoadjuvant therapies and pathological complete response as a biomarker of survival in human epidermal growth factor receptor-2 enriched breast cancer - A retrospective cohort study.
      ,
      • Spring L.M.
      • et al.
      Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis.
      , these results are non-representative of ILC disease: Cortazar et al., illustrated that ILC demonstrates poor sensitivity to neoadjuvant chemotherapies (NAC) and no impact on OS outcomes overall [pCR rate in ILC: 7.8%, HR: 0.93 (95% CI: 0.50 – 1.70)]
      • Cortazar P.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
      . While achieving a pCR to NAC is perceived to carry prognostic significance in certain breast cancer molecular subtypes
      • Davey M.G.
      • et al.
      Clinicopathological response to neoadjuvant therapies and pathological complete response as a biomarker of survival in human epidermal growth factor receptor-2 enriched breast cancer - A retrospective cohort study.
      ,
      • Spring L.M.
      • et al.
      Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis.
      , the ILC histological subtype fails to corroborate such results, based on the work of the Collaborative Trials on Neoadjuvant Breast Cancer (CTNeoBC)
      • Cortazar P.
      • et al.
      Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
      . Therefore, perhaps it is somewhat unsurprising that prescribing chemotherapy failed to improve the long-term survival observed in the current analysis of over 28,000 patients treated for ILC. Thus, these results indicate a more judicious approach to systemic therapy prescription in ILC is warranted in future.
      Prior to this study, the long-term impact of prescribing systemic chemotherapy to improve oncological and survival outcomes in early-stage ILC had not previously been evaluated. Therefore, this meta-analysis provides novel data highlighting the limited premise for using such therapies to improve DFS (OR: 0.89, 95% CI: 0.65 – 1.23) and OS (OR: 0.92, 95% CI: 0.72 – 1.18) at 10-years outcomes following treatment and over the full trajectory of the included studies [DFS - HR: 1.01 (95% CI: 0.78 – 1.31), OS - HR: 1.07 (95% CI: 0.89 – 1.27)]. These are interesting findings which speak to the tendency of ILCs to develop larger, more indolent cancers which are ER+/PgR+, with lower 21-gene expression assay recurrence scores (RS) and metastatic potential, which derive limited benefit from chemotherapy
      • Davey M.G.
      • et al.
      Clinicopathological correlates, oncological impact, and validation of Oncotype DX™ in a European Tertiary Referral Centre.
      • Makower D.
      • et al.
      The 21-gene recurrence score in early non-ductal breast cancer: a National Cancer Database analysis.
      • Truin W.
      • et al.
      Differences in Response and Surgical Management with Neoadjuvant Chemotherapy in Invasive Lobular Versus Ductal Breast Cancer.
      . The modern breast cancer treatment paradigm for early-stage ER+/HER2- disease relies heavily upon multigene expression assays (such as RS) to guide therapeutic decision making surrounding chemoendocrine therapies
      • Kalinsky K.
      • et al.
      21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.
      ,
      • Sparano J.A.
      • et al.
      Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
      ,
      • Paik S.
      • et al.
      A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer.
      , which of course may influence ILC management prospectively: Makower et al. previously demonstrated that just 7.2% of patients with ILC had high-risk RS (RS 26-100) versus 16.9% of those with ductal histology in their analysis using patients from the National Cancer Database
      • Makower D.
      • et al.
      The 21-gene recurrence score in early non-ductal breast cancer: a National Cancer Database analysis.
      . Furthermore, this analysis illustrated no survival advantage associated with chemotherapy use in ILC (HR: 0.99, 95% CI: 0.70 – 1.39) when adjusted for age, race, ethnicity, rurality, median income and educational level of area of residence, RS, tumour size, grade, nodal involvement, and Charlson-Deyo comorbidity index. Interestingly, patients in the aforementioned study with RS 11-25 being treated for ILC disease were more likely to receive adjuvant chemotherapy than other histological subtypes, which is best explained by the overestimated benefit of such therapies in the setting of larger ILC cancers by the medial oncology community
      • Pivot X.
      • et al.
      In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy?.
      . As evidenced by the recent TAILORx and RxPONDER trials
      • Kalinsky K.
      • et al.
      21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.
      ,
      • Sparano J.A.
      • et al.
      Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
      , reliance upon traditionally actionable clinicopathological parameters (such as tumour size and nodal status) to guide chemoendocrine prescription in ER+ disease is now becoming almost obsolete. Furthermore, trials such as RxPONDER were not powered to estimate the survival advantage of chemoendocrine therapies based on subgroups, such as histological subtypes
      • Kalinsky K.
      • et al.
      21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.
      . The evidence reported in the current analysis illustrates that the case of lobular histology provides an obvious exception to this concept, with limited premise to prescribe chemotherapy for cases of ILC, unless directed by multigene expression assays.
      There are currently no prospective randomised clinical trials attempting to ascertain the value of chemotherapy use on long-term oncological and survival outcomes in ILC. The poor response previously observed in ILC to NAC in prospective clinical trials
      • Reitsamer R.
      • et al.
      Pathological complete response rates comparing 3 versus 6 cycles of epidoxorubicin and docetaxel in the neoadjuvant setting of patients with stage II and III breast cancer.
      ,
      • Loibl S.
      • et al.
      Surgical procedures after neoadjuvant chemotherapy in operable breast cancer: results of the GEPARDUO trial.
      precludes efforts to design such studies which may inform the long-term impact of cytotoxic chemotherapy on survival outcomes for those with ILC, and further exacerbates the research inequity surrounding the management of this common, understudied cancer subtype. Until this partiality is recognised and subsequent re-evaluation is performed, reliance upon studies such as the current meta-analysis to provide insights into the optimal managerial strategy for ILC will remain.
      The current study suffers from several limitations. Firstly, all the included studies are retrospective in design, rendering this data subject to potential selection, confounding and ascertainment biases. For example, the potential for confounding factors such as tumour size, degree of nodal burden, and tumour biology to influence therapeutic decision-making regarding systemic therapies must be considered when interpreting the results of this analysis. Secondly, to build on this previous limitation, just two included studies
      • Hu G.
      • et al.
      Adjuvant chemotherapy could not bring survival benefit to HR-positive, HER2-negative, pT1b-c/N0–1/M0 invasive lobular carcinoma of the breast: a propensity score matching study based on SEER database.
      ,
      • Watanuki R.
      • et al.
      Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.
      [representing 27.6% of the entire patient group (7,782/28,218)] performed propensity matching to accurately inform the impact of systemic chemotherapy on outcome. The remaining seven studies failed match ILC cases based on clinicopathological information, limiting the robustness of these results. Thirdly, this analysis failed to illustrate the survival outcomes according to ILC subgroups (e.g.: pleomorphic variants), with all patients classified under the umbrella term ‘ILC’. Finally, current expert consensus statements and guidelines do not recommend histological subtype to guiding therapeutic decision-making in ER+/HER2- disease and emphasise the importance of multigene expression assays for adjuvant chemoendocrine prescription in early-stage ER+/HER2-
      • Goldhirsch A.
      • et al.
      Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
      ,
      • Senkus E.
      • et al.
      Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      . Adherence to such guidelines is of critical importance, irrespective of histological tumour subtype.
      This systematic review and meta-analysis illustrates no long-term oncological or survival advantage associated with chemotherapy prescription in the setting of early-stage ILC breast cancer. Survival outcomes 10-years following treatment were similar for those receiving chemotherapy and their counterparts, highlighting the chemoinsensitive nature of ILC. In the absence of well-designed, prospective clinical trials evaluating the impact of chemotherapy on long-term outcomes in ILC, these results should be considered by the multidisciplinary team when deciding on the value of systemic chemotherapy prescription in these cases.

      Sources of funding

      MGD received funding from the National Breast Cancer Research Institute, Ireland.

      Category

      Systematic Review article – This manuscript is not based on a communication to a society or meeting

      Appendix. Supplementary materials

      References

        • Wilson N.
        • et al.
        Lobular Breast Cancer: A Review.
        Frontiers in Oncology. 2021; 10
        • Thomas M.
        • et al.
        Invasive lobular breast cancer: A review of pathogenesis, diagnosis, management, and future directions of early stage disease.
        Semin Oncol. 2019; 46: 121-132
        • Sung H.
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • Mouabbi J.A.
        • et al.
        Invasive lobular carcinoma: an understudied emergent subtype of breast cancer.
        Breast Cancer Res Treat. 2022;
        • Luveta J.
        • et al.
        Invasive Lobular Breast Cancer as a Distinct Disease: Implications for Therapeutic Strategy.
        Oncology and therapy. 2020; 8: 1-11
        • Zengel B.
        • et al.
        Comparison of the clinicopathological features of invasive ductal, invasive lobular, and mixed (invasive ductal + invasive lobular) carcinoma of the breast.
        Breast Cancer. 2015; 22: 374-381
        • Korhonen T.
        • et al.
        The impact of lobular and ductal breast cancer histology on the metastatic behavior and long term survival of breast cancer patients.
        Breast. 2013; 22: 1119-1124
        • Rakha E.A.
        • et al.
        Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes.
        Eur J Cancer. 2008; 44: 73-83
        • O'Connor D.J.
        • et al.
        Differences in sensitivity to neoadjuvant chemotherapy among invasive lobular and ductal carcinoma of the breast and implications on surgery-A systematic review and meta-analysis.
        Breast. 2022; 61: 1-10
        • Cocco D.
        • et al.
        Invasive Lobular Breast Cancer: Data to Support Surgical Decision Making.
        Ann Surg Oncol. 2021; 28: 5723-5729
        • Sharma S.D.
        • et al.
        Surgical management of lobular carcinoma from a national screening program: a retrospective analysis.
        Eur J Surg Oncol. 2015; 41: 79-85
        • Chen Z.
        • et al.
        Invasive lobular carcinoma of the breast: A special histological type compared with invasive ductal carcinoma.
        PLoS One. 2017; 12e0182397
        • Ciriello G.
        • et al.
        Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.
        Cell. 2015; 163: 506-519
        • Christgen M.
        • et al.
        E-cadherin to P-cadherin switching in lobular breast cancer with tubular elements.
        Modern Pathology. 2020; 33: 2483-2498
        • Teo K.
        • et al.
        E-cadherin loss induces targetable autocrine activation of growth factor signalling in lobular breast cancer.
        Sci Rep. 2018; 8: 15454
        • De Schepper M.
        • et al.
        Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer.
        Modern Pathology. 2022;
        • Jacobs C.
        • et al.
        Treatment choices for patients with invasive lobular breast cancer: a doctor survey.
        J Eval Clin Pract. 2015; 21: 740-748
        • Kalinsky K.
        • et al.
        21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.
        New England Journal of Medicine. 2021; 385: 2336-2347
        • Sparano J.A.
        • et al.
        Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
        New England Journal of Medicine. 2018; 379: 111-121
        • Moher D.
        • et al.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        Bmj. 2009; 339: b2535
        • Stroup D.F.
        • et al.
        Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
        Jama. 2000; 283: 2008-2012
        • Stang A.
        Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
        Eur J Epidemiol. 2010; 25: 603-605
        • Kim H.Y.
        Statistical notes for clinical researchers: Chi-squared test and Fisher's exact test.
        Restor Dent Endod. 2017; 42: 152-155
        • Chen X.H.
        • et al.
        21-gene recurrence score and adjuvant chemotherapy decisions in patients with invasive lobular breast cancer.
        Biomark Med. 2019; 13: 83-93
        • de Nonneville A.
        • et al.
        Adjuvant chemotherapy in lobular carcinoma of the breast: a clinicopathological score identifies high-risk patient with survival benefit.
        Breast Cancer Res Treat. 2019; 175: 379-387
        • Hu G.
        • et al.
        Adjuvant chemotherapy could not bring survival benefit to HR-positive, HER2-negative, pT1b-c/N0–1/M0 invasive lobular carcinoma of the breast: a propensity score matching study based on SEER database.
        BMC Cancer. 2020; 20: 136
        • Iorfida M.
        • et al.
        Invasive lobular breast cancer: subtypes and outcome.
        Breast Cancer Res Treat. 2012; 133: 713-723
        • Jenkins J.A.
        • et al.
        The 70-gene signature test as a prognostic and predictive biomarker in patients with invasive lobular breast cancer.
        Breast Cancer Res Treat. 2022; 191: 401-407
        • Marmor S.
        • et al.
        Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast.
        Cancer. 2017; 123: 3015-3021
        • Metzger-Filho O.
        • et al.
        Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.
        The oncologist. 2019; 24: e441-e449
        • Watanuki R.
        • et al.
        Impact of neoadjuvant and adjuvant chemotherapy on invasive lobular carcinoma: A propensity score-matched analysis of SEER data.
        Breast J. 2020; 26: 1765-1770
        • Truin W.
        • et al.
        Effect of adjuvant chemotherapy in postmenopausal patients with invasive ductal versus lobular breast cancer.
        Ann Oncol. 2012; 23: 2859-2865
        • Cristofanilli M.
        • et al.
        Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes.
        J Clin Oncol. 2005; 23: 41-48
        • Davey M.G.
        • et al.
        Clinicopathological response to neoadjuvant therapies and pathological complete response as a biomarker of survival in human epidermal growth factor receptor-2 enriched breast cancer - A retrospective cohort study.
        Breast. 2021; 59: 67-75
        • Spring L.M.
        • et al.
        Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis.
        Clin Cancer Res. 2020; 26: 2838-2848
        • Cortazar P.
        • et al.
        Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
        Lancet. 2014; 384: 164-172
        • Davey M.G.
        • et al.
        Clinicopathological correlates, oncological impact, and validation of Oncotype DX™ in a European Tertiary Referral Centre.
        Breast J. 2021; 27: 521-528
        • Makower D.
        • et al.
        The 21-gene recurrence score in early non-ductal breast cancer: a National Cancer Database analysis.
        npj Breast Cancer. 2022; 8: 4
        • Truin W.
        • et al.
        Differences in Response and Surgical Management with Neoadjuvant Chemotherapy in Invasive Lobular Versus Ductal Breast Cancer.
        Ann Surg Oncol. 2016; 23: 51-57
        • Paik S.
        • et al.
        A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer.
        New England Journal of Medicine. 2004; 351: 2817-2826
        • Pivot X.
        • et al.
        In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy?.
        Oncologist. 2015; 20: 344-350
        • Reitsamer R.
        • et al.
        Pathological complete response rates comparing 3 versus 6 cycles of epidoxorubicin and docetaxel in the neoadjuvant setting of patients with stage II and III breast cancer.
        Anti-Cancer Drugs. 2005; 16
        • Loibl S.
        • et al.
        Surgical procedures after neoadjuvant chemotherapy in operable breast cancer: results of the GEPARDUO trial.
        Ann Surg Oncol. 2006; 13: 1434-1442
        • Goldhirsch A.
        • et al.
        Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
        Ann Oncol. 2013; 24: 2206-2223
        • Senkus E.
        • et al.
        Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi7-v23