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Abstract

Introduction

Chemotherapy is used frequently in the neoadjuvant setting for breast cancers, most commonly triple negative and human epidermal growth factor receptor 2 (HER-2) positive breast cancer. Certain hormone positive HER-2 negative cancers known as luminal B have shown response to adjuvant chemotherapy and can be considered in the neoadjuvant setting. This meta-analysis reviews survival outcomes in neoadjuvant chemotherapy in comparison to adjuvant in luminal B breast cancer.

Methods

PubMed, Medline, and Embase were accessed on the 31^st of January 2024 to complete this systematic review and meta-analysis. All study types were included. Studies included compared survival rates in luminal B breast cancer patients in the neoadjuvant and adjuvant setting. All regimens of chemotherapy were included. Studies were included if they had at least median of 48 months follow up. Studies were excluded if they were non-comparative or did not report survival rates.

Results

Two retrospective analyses comparing neoadjuvant and adjuvant chemotherapy were found from this systematic review, with a total of 4575 patients included. Of the 4575 patients, 679 received neoadjuvant chemotherapy (14.84%). Meta-analysis of these studies identified a non-significant trend of increased overall survival in the adjuvant chemotherapy arm with a hazard ratio of 1.85, confidence interval 0.98 – 3.48, (P value 0.058).

Discussion

This meta-analysis revealed a paucity of data in the comparison of neoadjuvant to adjuvant chemotherapy in luminal B breast cancer patients. Both studies identified were of a retrospective nature, and further research in this field should be considered.

Keywords

luminal b hormone positive HER2 negative breast cancer neoadjuvant chemotherapy overall survival

Introduction

The use of chemotherapy in locally advanced breast cancer has been well established, with roles in the pre-operative and postoperative setting.¹ Neoadjuvant chemotherapy (NACT) may provide several benefits including reducing tumour size to increase rates of breast conserving surgery (BCS) over mastectomy, downstaging axillary disease, and evaluating tumour response to chemotherapy.² Patients undergoing NACT who achieve a pathological complete response (pCR) have shown a benefit in overall survival (OS) in comparison to patients with residual disease,³ however there is no statistically significant OS benefit in comparison to adjuvant therapy.⁴ In a meta-analysis performed by The Early Breast Cancer Trialists’ Collaborative Group, which compared outcomes of neoadjuvant vs adjuvant therapy in breast cancer, BCS rates were higher in the neoadjuvant setting, but showed no benefit in breast cancer mortality rates.⁵

In clinical practice, the decision for NACT in early or locally advanced breast cancer is heavily dependent on tumour biology. In human epidermal growth factor receptor 2 (HER2) positive breast cancer, multiple international guidelines recommend NACT in combination with anti-HER2 directed therapy, or NACT in combination with immune-checkpoint inhibitor therapy for triple negative breast cancer (TNBC). In the case of hormone receptor (HR)-positive/HER2-negative disease, also known as a luminal subtype, there is not a clear directive to provide neoadjuvant therapy, however NACT can be considered to reduce tumour burden in certain cases.^6-8

The Luminal subtype can be further separated to Luminal A or B, based on their individual HR status (estrogen and progesterone), and proliferative index (Ki67).⁹ Luminal B breast cancer is defined as having variable hormone receptor positivity, are higher Nottingham histologic score as well as an increased Ki67%, in comparison to Luminal A cancers that have high hormone receptor positivity, lower Nottingham histologic score and lower Ki67%.⁷ Luminal B breast cancer tend to have more aggressive characteristics than Luminal A, with an increased risk of axillary nodal involvement of 50% compared to 10%,¹⁰ and a slightly higher risk of locoregional recurrence of 1.5%-8.7%, compared to 0.8%-8% for Luminal A cancers.¹¹ Luminal B breast cancers are less endocrine sensitive, when compared to the Luminal A sub-type, which reduces efficacy of adjuvant hormone therapy. Patients with luminal breast cancer receiving adjuvant endocrine therapy have reduced risk of recurrence or death.¹² Luminal B breast cancers have lower positivity for oestrogen receptor and variable or negative progesterone receptor positivity, therefore may have a lower response to endocrine therapy in comparison to luminal A.

In most cases luminal breast cancers will receive upfront surgery, however, in light of these features, Luminal B cancers are more readily considered for NACT than Luminal A tumours.¹³ Whilst Luminal cancers are associated with lower rates of pCR in comparison to HER2 + cancers and TNBC in the neoadjuvant setting, evidence indicates a higher pCR rate in Luminal B cancers (11.4%) than Luminal A (6.2%), reflective of a more pro-proliferative underlying tumour biology and therefore increased chemosensitivity.¹⁴

Despite multiple national guidelines supporting the utilization of chemotherapy, none directly recommend the use of NACT over adjuvant chemotherapy in the treatment of luminal B breast cancer.^6-8 We performed a meta-analysis of Luminal B breast cancer patients undergoing neoadjuvant or adjuvant chemotherapy to compare OS rates. It is hypothesized that there is not enough data to support this, identifying a need for further research in this area.

Methods

Search Strategy

A systematic review and meta-analysis were performed using the updated PRISMA guidelines.¹⁵ A search was conducted using PubMed, Embase and Medline databases, carried out on the 31st of January 2024. The following advanced search strategy was used: (Luminal OR ER + OR ER-positive OR estrogen receptor positive or hormone receptor positive) AND (neoadjuvant OR preoperative chemotherap* OR pre-operative chemotherap*) AND (breast AND (cancer OR malignan*)). Studies were limited to the English language. Additional studies were sought for within reference lists of all relevant studies identified. This systematic review and meta-analysis was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), reference number: INPLASY202590103. A protocol for this study is available on request but has not been published.

Inclusion Criteria

All study types were included, with Luminal B breast cancer patients aged 18 or above published within the past 25 years (January 1999 – January 2024). Studies were included if the intervention was neoadjuvant breast cancer with a comparator adjuvant arm. Studies were included if the outcomes of the study included OS, disease free survival (DFS), locoregional recurrence rate, overall response rates or pCR rates. Studies were included if they reported on outcomes of 5 years or greater.

Exclusion Criteria

Studies were excluded if there was no clear comparator adjuvant arm, if the molecular sub-type was not specifically documented and if neoadjuvant and adjuvant chemotherapy subgroup were not compared. Studies were also excluded if outcomes of survival, recurrence, or pathologic response as above were not reported.

Data Extraction

Two authors performed the database search and extracted data from relevant studies independently. Titles and abstracts were screened for relevance, and full studies were then selected for review based on screening. Any conflicts were resolved by discussion between data extractors and senior co-authors. Data points extracted were study design, study location, study date, average patient age, average length of follow up, number of patients in the neoadjuvant and adjuvant groups, stage of disease of patients included, pCR rate, OS, DFS, overall response rate, and locoregional recurrence rate. Data was extracted manually by each author and compared.

Statistical Analysis

A random-effects model was used to generate a pooled hazard ratio and 95% confidence interval. A combined hazard ratio incorporating both stage I-II and III patients was generated for one of the included studies. Cochran’s Q statistic was used to test heterogeneity of the studies, whereby a P value of less than 0.10 indicated heterogeneity. The I² statistic was used to quantify the degree of heterogeneity, such that values of 25%, 50% and 75% indicated low, medium, and high respectively.

Risk of Bias Assessment

To assess for risk of bias, the ROBINS-I tool¹⁶ will be used to quantify risk of non-randomised studies, for randomised controlled trials identified, the RoB-2 tool¹⁷ will be used. Two authors will independently assess for risk of bias of included studies, and if required senior co-authors will review and resolve conflicts between independent risk assessments. The Robvis tool¹⁸ was used to generate a summary of bias plot.

Results

Out of the 11 910 citations screened by the search strategy, only two studies were deemed suitable to include in the meta-analysis (Figure 1). These studies were retrospective cohort studies which compared neoadjuvant and adjuvant chemotherapy in breast cancer patients and reported OS outcomes. A study performed by Chen et al,¹⁹ was excluded as it stratified Luminal B patients with a pCR following neoadjuvant therapy separately to those with an incomplete pathological response in comparing survival outcomes to those undergoing adjuvant therapy. In addition, this subgroup survival analysis related to breast cancer specific and disease-free survival rather than OS.

Figure 1.

Study Selection Flow Chart

The participants in both included studies were stratified by subtype, which included a Luminal B or hormone-positive and HER2-negative subgroup. Yang et al,²⁰ was conducted in China, with data collected from the Peking University People’s Hospital from 2000-2008. Zhang et al²¹ was conducted in the USA and used data from the Surveillance, Epidemiology and End Results (SEER) database, collected from 2010-2017. Both these studies reported on OS. Both were appraised as valid for inclusion, in accordance with the PRISMA guidelines.¹⁵The study characteristics for the included studies are summarized in Table 1.

Table 1.

Study Characteristics

First author	Year	Study type	Country	Data source	Median follow-up (mo)	NAC (n)	AC (n)	Outcomes measured
Zhang	2023	RCS	USA	SEER database (2010-2017)	48	1771	6724	OS, DFS
Yang	2018	RCS	China	Peking university People’s hospital (2000-2008)	78	201	205	OS

RCS, retrospective cohort study; SEER, Surveillance, Epidemiology and End Results; NAC, neoadjuvant chemotherapy; AC, adjuvant chemotherapy; OS, overall survival; BCSS, breast cancer specific survival; DFS, disease-free survival.

Of the patients with Luminal B breast cancer, a total of 679 patients underwent NACT and a total of 3896 patients underwent adjuvant chemotherapy. A summary of the molecular subtypes of the study participants is shown in Table 2. The median follow-up in both studies was 78 and 48 months, respectively. Regarding OS, patients in Zhang et al, were stratified into stage I-II and stage III subgroups and a combined hazard ratio (1.27, 95% CI 0.92-1.74, P = 0.148) was generated to include all patients.

Table 2.

Molecular Subtypes of Study Participants

First author	Luminal B or HR+/Her2-		Her2+ (n)		Triple negative (n)
First author	NAC	AC	NAC	AC	NAC	AC
Zhang	629	3806	655	1556	434	1249
Yang	50	90	15	15	36	31

NAC, neoadjuvant chemotherapy; AC, adjuvant chemotherapy.

Meta-analysis of the two studies showed a non-significant trend of improved OS favouring adjuvant chemotherapy over NACT in Luminal B cancer patients, with a pooled HR of 1.85 (95% CI 0.98-3.48, P = 0.058). (Figure 2). There was no significant heterogeneity between these studies (I² = 46.34, P = 0.17).

Figure 2.

Overall Survival Comparing Neoadjuvant and Adjuvant Chemotherapy in Luminal B Patients. Meta-Analysis Comparing Overall Survival Between Luminal B Patients Undergoing Neoadjuvant Versus Adjuvant Chemotherapy. A Hazard Ratio With 95% Confidence Interval and P-value is Demonstrated for Each Study. Heterogeneity Test I² = 46.34, P = 0.17

Both studies were assessed for risk of bias using the ROBINS-I tool with both studies demonstrating a serious risk of bias (Figure 3).

Figure 3.

ROBINS-I Risk of Bias Assessment

Discussion

The most pertinent finding from this meta-analysis is the paucity of data available to compare outcomes in neoadjuvant and adjuvant chemotherapy in Luminal B breast cancers. Over several thousand journal articles were identified from the search strategy, with only two retrospective analyses meeting the inclusion criteria. Conversely to other sub-types of breast cancer, which have a well-established database, there is a lack of data to support the use of NACT for luminal B breast cancer. Whilst there was a trend favoring the adjuvant therapy arm, this was not statistically significant in the pooled analysis. This trend observed may be due to a selection bias of candidates for neoadjuvant therapy, given the studies were retrospective in nature. Patients deemed higher risk of recurrence may have been selected in these studies for NACT over less aggressive tumours. Furthermore, the studies included utilized different chemotherapy regimens within and between studies, therefore introducing treatment bias and confounding significance of pooled analysis, where there is already statistical insignificance. The lack of power and the retrospective nature of the studies identified cannot support any stance in clinical practice and highlights that further studies comparing matched neoadjuvant and adjuvant cohorts must be undertaken.

Tumour downsizing is a key advantage of NACT, as it allows for greater rates of BCS relative to mastectomy.^22-24 For HER2+ and TNBC, the common regression pattern is described as concentric tumour shrinkage (CTS), which may be associated with pCR.^25,26 CTS allows excision of a smaller tumour volume, with minimal concerns regarding residual tumour in the original tumour footprint. A meta-analysis by Zheng et al,²⁷ evaluated the rates of CTS across all subtypes and receptor statuses. This reinforced the greater rates of CTS for TNBC and HER2+ (66.2% and 59.0%, respectively), compared to Luminal A and B (29.7% and 47.2%, respectively). When considering HR only, HR-negative cancers have a greater rate of concentric shrinkage compared to HR-positive (63.1% vs 45.7%, OR 2.32). This is in line with the concept of limited surgical excision whereby only breast tissue with the pre-treatment localization clip is removed for those with a pCR without pursuing clearance of margins beyond the tumour bed. One retrospective study evaluating 406 women with invasive cancer who had a pCR after NACT showed no difference in 5-year OS, disease-free survival and recurrence-free survival for those with close (<1 mm), wider (>1 mm) or unknown margins.²⁴ While larger studies and longer-term data are still needed to support this, this has the potential to improve breast conservation and cosmesis for patients with a pCR without compromising oncologic outcomes and safety.

Luminal B cancers have an unpredictable morphological response to NACT, with a greater risk of a nodular or mixed pattern of response. In the case of fragmentation or non-concentric response, resection margins are unlikely to be changed, resulting in the same surgical plan prior to NACT. Though some have postulated modified non-concentric shrinkage modes to encourage BCS, high rates of short-term recurrence or metastasis have been reported (29.4% at median 77 months).²⁸ This raises concern of a “false negative margin” and is why in similar situations, the St Gallen Consensus is for “generous” margins to decrease this likelihood.²⁹ Subsequently, with such an unpredictable response to NACT, it may not be appropriate for Luminal B cancers to receive NACT solely to improve rates of BCS.

NACT for breast cancer affords time for genetic testing, which may influence surgical planning. In a select group of breast cancer patients with; high Nottingham histologic score, cases of recurrent disease, or strong family history, genetic testing may be warranted to assess for variants of genes that may increase risk of developing breast cancer. These risk factors can be calculated using the Manchester score, which is used in clinical practice to direct use of genetic testing.³⁰ In Australia, turnaround time for genetic testing ranges from 4 to 8 weeks.^31,32 Given this wait time, referring a patient for neoadjuvant therapy affords time for results to be returned prior to performing surgery. If gene testing were found to be positive, this may influence surgical decision making. Whilst Breast Cancer Gene 1 (BRCA1) is most commonly associated with TNBC,³³ mutations in the Breast Cancer Gene 2 (BRCA2) and Partner and Localizer of BRCA2 (PALB2) have been associated with Luminal B breast cancers.^34,35 Rates of luminal B cancer in those with BRCA2-associated breast cancer mirrors the general population incidence and is reported as high as 55.3%.^34,35 In the correct setting, neoadjuvant therapy for Luminal B breast cancers may afford clinicians adequate time to determine genetic status of a patient to guide surgical planning.

There have been significant advances in chemotherapy that continue to change the landscape of type and timing of chemotherapy given in breast cancer. In clinical practice either in the adjuvant or neoadjuvant setting, regimens including anthracyclines, taxanes and cyclophosphamide are usually considered.³⁶ Most recently, cyclin kinase dependent 4 or 6 (CDK4/6) inhibitors such as Ribociclib and Abemaciclib have become part of the standard treatment approach for both high risk localized (adjuvant) and metastatic HR-positive/HER2-negative breast cancers in combination with endocrine therapy. There is now robust evidence supporting improvements in progression-free survival (PFS), OS in metastatic HR-positive/HER2-negative breast cancer³⁷ and improved DFS in the adjuvant setting for high risk localized HR-positive/HER2-negative breast cancers compared to adjuvant endocrine therapy alone.^38,39 The PALOMA-1/TRIO-18 trial has investigated CDK4/6 inhibitors in the neoadjuvant setting, which demonstrated significant prolongation in PFS. This study lacked power to report on OS with statistical significance, but data suggests no detriment to OS rates with the addition of a CDK4/6 to neoadjuvant endocrine therapy.⁴⁰

Decision making for NACT is multifactorial, considering both patient and tumour factors. Concerningly, not all Luminal B patients may benefit from chemotherapy. Genetic profiling of a tumour can provide insight whether chemotherapy would be effective, impacting its’ recommendation. A validated 21-gene expression assay, Oncotype DX, can be used in up to T3 and/or N1 cases to stratify risk of recurrence in the post-menopausal, and has shown safety in forgoing chemotherapy in low risk patients - as well as non-inferiority of endocrine therapy alone in intermediate risk patients.^41,42 The assay has also been shown in a retrospective analysis performed by Pease et al⁴³ to demonstrate a statistically significant correlation between high-risk patients and higher rates of pCR. This is significant since higher rates of pCR have been shown to be associated with increased rates of OS.³ However, it is important to consider aligning NACT with outcomes of the assay to avoid overtreatment, since evidence suggests use of chemotherapy can be reduced by 28% in Oncotype DX tested patients.⁴⁴ The inclusion criterion does highlight a cohort of patients that are not “Oncotype appropriate”, ie, T4 and/or N2, and thus should routinely consider chemotherapy, whether neoadjuvant or adjuvant.

Conclusion

The significant lack of evidence in this sphere is the main limitation of this study. This meta-analysis was only able to identify two retrospective studies, with differences of chemotherapy regimen, temporal association, and lack of randomization observed. The characteristics of these studies preclude statistical analysis of value and pooled ratios observed need to be scrutinized given the nature of these studies. Therefore, there is no possibility of commenting on survival outcomes in NACT, nor whether evidence supports or refutes the use of NACT in Luminal B breast cancers. Multiple nuances in clinical decision making were explored regarding potential utilization of neoadjuvant chemotherapy for luminal B breast cancers, however non inferiority of survival benefit must first be identified such that neoadjuvant therapy can be given safely. This meta-analysis highlights the importance of further research in this area, with the development of prospective head-to-head analyses of neoadjuvant and adjuvant chemotherapy in Luminal B breast cancers.

Footnotes

ORCID iD

Luke Bromley

Ethical Considerations

An ethics statement is not applicable as this study is based exclusively on published literature.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Appendix

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Neoadjuvant vs. Adjuvant Chemotherapy for Luminal B Breast Cancer: A Systematic Review and Meta-Analysis – Where is the Evidence?

Abstract

Introduction

Methods

Results

Discussion

Keywords

Introduction

Methods

Search Strategy

Inclusion Criteria

Exclusion Criteria

Data Extraction

Statistical Analysis

Risk of Bias Assessment

Results

Discussion

Conclusion

Footnotes

ORCID iD

Ethical Considerations

Funding

Declaration of conflicting interests

Appendix

References