Differences between invasive lobular and invasive ductal carcinoma of the breast: results and therapeutic implications

Abstract

Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC): ILC differs from invasive ductal carcinoma (IDC) in its clinicopathological characteristics and responsiveness to systemic therapy. From the clinical standpoint, data suggest that ILC derives a distinct benefit from systemic therapy compared to IDC. In addition, comprehensive molecular analyses have been reported for ILCs, confirming that these tumors have specific genomic profiles compared to IDC. Despite these differences, clinical trials and practical clinical guidelines tend to treat BC as a single entity. Here we discuss these clinical and molecular data and their therapeutic implications.

Introduction

Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer (BC), and accounts for approximately 10% of all BCs [Li et al. 2003]. This subtype differs in epidemiology, molecular alterations, clinicopathologic aspects and natural history from invasive ductal carcinoma (IDC), which qualifies as the most common subtype of BC [Rakha and Ellis, 2010].

The classical form of ILC is characterized morphologically by small, noncohesive cells that infiltrate the stroma in a single-file pattern [Rakha and Ellis, 2010]; this noncohesive phenotype is a consequence of the deregulation of cell–cell adhesion properties, primarily driven by the lack of E-cadherin expression. Approximately 90% of ILCs lack E-cadherin protein expression – and this feature has thus become a hallmark of ILC. E-cadherin deregulation is driven by genomic alterations that target its CDH1 gene (located at chromosome 16q22.1) [McCart Reed et al. 2015]. Additionally, a number of variants have been described, based on their distinct architecture (alveolar, solid and trabecular) or cytological features (pleomorphic, apocrine, histiocytoid, and signet ring: these ILC subtypes are now collectively referred to as ‘mixed-nonclassic’ ILC) [Iorfida et al. 2012].

Although ILC typically displays features associated with a good prognosis (low to intermediate grade, low Ki-67 expression, positive estrogen receptor (ER) expression and absence of HER2 protein overexpression or amplification [Rakha and Ellis, 2010], some studies suggest that overall long-term outcomes of ILC may be worse than those for stage-matched IDC [Rakha and Ellis, 2010; Iorfida et al. 2012]. Importantly, ILCs are more prone to spread to gastrointestinal, peritoneal and ovarian tissues [Rakha and Ellis, 2010].

Recently, two groups have undertaken comprehensive molecular analyses of ILCs and confirmed that these tumors have distinct genomic profiles compared to IDCs. Besides verifying that ILCs exhibit a high frequency of CDH1 mutations, these reports also show more frequent loss of phosphatase and tensin homolog (PTEN), activation of AKT, and mutations in TBX3 and FOXA1 in these tumors compared with IDCs [Ciriello et al. 2015; Desmedt et al. 2016]. Here we address the issue that, despite BC being treated as a single entity in clinical trials, these molecular differences have therapeutic implications.

Chemotherapy benefit

Neoadjuvant chemotherapy is the standard of care for patients with locally advanced BC. Although no difference in disease-free survival (DFS) and overall survival (OS) outcome relative to the use of adjuvant treatment, neoadjuvant chemotherapy induces tumor downstaging, and increases rates of breast-conserving surgery (BCS); the neoadjuvant approach also provides a unique opportunity to monitor the tumor’s chemosensitivity in vivo. In this context, the neoadjuvant setting has been used in several retrospective studies, and has consistently shown that patients with IDC derive greater benefit from chemotherapy than do those with primary ILC [Mathieu et al. 2004; Cristofanilli et al. 2005; Tubiana-Hulin et al. 2006; Lips et al. 2012; Delpech et al. 2013].

In particular, Delpech and colleagues retrospectively evaluated data from 1895 patients who had stage I–III, ER-positive BC and who additionally received neoadjuvant chemotherapy at the University of Texas MD Anderson Cancer Centre, USA [Delpech et al. 2013]. The aim of the study was to compare surgical benefit and chemotherapy sensitivity in patients with ILC (n = 177) in the context of their pathological response rates, surgical margin status, and rates of BCS. The most commonly used regimen (80%) was a combination of anthracycline and taxane, which was used with equal frequency in both groups. Importantly, trastuzumab use was more common in IDC. Although the authors observed a significant downstaging (p < 0.001) after neoadjuvant chemotherapy compared with baseline in both histological types, fewer ILCs had lower tumor T stage (TNM criteria) compared with the IDC group (41% versus 64%, respectively; p < 0.0001). Positive or close (⩽2 mm) surgical resection margins were significantly more frequent in ILC patients (19% versus 11%; p < 0.001), and this remained significant even after multivariate analysis (OR = 1.82; 95% CI 1.13–2.93; p = 0.01). At the end, BCS was less frequent in ILC patients than in IDC patients (19% versus 34%; p < 0.001), and histology remained an independent predictor of mastectomy (OR = 1.86; 95% CI 1.15–2.99; p = 0.01). In univariate analysis, invasive lobular histology was also associated with significantly lower pathological complete response (pCR) rates (3.5% versus 14%; p < 0.001); however, this feature was no longer significant in multivariate analysis. This finding differs from a previous report that suggests significantly lower pCR rates in ILC [Cristofanilli et al. 2005].

Because the majority of patients with ILC have low-grade ER positive tumors, they are unlikely to derive significant benefit from either adjuvant or neoadjuvant chemotherapy; thus, efforts to develop reliable biomarkers that can identify the fraction of patients that truly derive benefit from cytotoxic agents are critical.

In contrast to IDC, the prognostic value of standard histologic grade (HG) is not well established in ILC. Because ILC tumors lack tubule formation, approximately two-thirds of these tumors are classified as HG2, which is noninformative for making treatment decisions. Preliminary research with use of the genomic grade (GG) index, a 97-gene signature that improves HG classification in invasive breast carcinoma, revealed that a subset of ILC had a higher GG (GG3) [Metzger-Filho et al. 2013b]. In this series, 72% of the tumors were classified as standard HG2, but 78% of these cases could be reclassified with the use of the GG index (81% as GG1 and 19% GG3). This study also showed that the GG index signature adds prognostic information to classic clinicopathologic variables in patients with classical and pleomorphic ILC. Collectively, these findings point to a need for clinical trials that prospectively address the predictive role of the GG index on chemotherapy benefit.

Furthermore, several groups have published their experience with use of Oncotype Dx in patients with ILC. These reports show that, in contrast with IDC where up to 20% of cases can have a high recurrence score (RS), only rarely do ILC tumors (1.5%) are classified in the high risk group. [Wolf et al. 2008; Bomeisl et al. 2015; Conlon et al. 2015; Tsai et al. 2016]. Similar to IDCs, approximately 40% of ILCs have an intermediate RS. Of relevance, Conlon and colleagues showed that in pleomorphic ILC cases, the proportion of tumors with intermediate RS may even be higher compared with classical ILC (69 × 32%, respectively) [Conlon et al. 2015]. Until the results of prospective trials (such as the MINDACT or TAILORx trial) are available, the optimal management of the intermediate RS group remains unestablished.

Magnitude of benefit from use of trastuzumab

Overexpression or amplification of the HER2 gene occurs in 3–5% of classic ILC [Yu et al. 2011; Iorfida et al. 2012]. Furthermore, a number of studies suggest that patients with ILC variants, such as mixed-nonclassic ILC, have higher rates of HER2 positivity (8.0–9.8%) [Yu et al. 2011; Iorfida et al. 2012]. Despite HER2 positivity being an independent prognostic factor associated with worse survival outcomes for patients diagnosed with ILC [Iorfida et al. 2012], few available data describe the magnitude of benefit of anti-HER2 therapies in this particular subtype.

The magnitude of benefit of adjuvant trastuzumab in the subset of ILC was investigated in a retrospective analysis using data from a prospectively conducted phase III study the Herceptin Adjuvant (HERA) [Metzger-Filho et al. 2013c]. HERA compared 1 or 2 years on trastuzumab treatment to observations (after standard chemotherapy) in women with HER2-positive BC. The study demonstrated that treatment with adjuvant trastuzumab for 1 year is associated with significant benefit in terms of DFS and helped to define this drug as a standard of care in an adjuvant setting for patients with HER2-positive tumors [Piccart-Gebhart et al. 2005; Gianni et al. 2011]. HER2-positive ILCs account for 5.5% of the 3401 patients included in the study. In the ILC subpopulation, 97 patients were randomly assigned to receive 1 year of trastuzumab, and 90 patients were assigned to observation. In the IDC subgroup, 1611 patients were randomly assigned to receive 1 year of trastuzumab and 1602 patients were assigned to observation. No differences were found in the pattern of disease relapse or in the magnitude of trastuzumab benefit for the two groups of patients. Despite limited numbers, the results suggest a higher ER-positivity rate and lower HER2 copy number in patients with ILC than in those with IDC. An important limitation of this analysis is that HERA lacks a central pathology review for BC histologic subtypes and data are missing regarding ILC variants. However, from a clinical practice perspective, the following important messages from this study must be taken into consideration: (a) a diagnosis of ILC is not synonymous with HER2-negative disease and thus HER2 testing should also be carried out in these cases; (b) adjuvant trastuzumab for 1 year is recommended to patients diagnosed with early-stage, HER2-positive ILC; and (c) the magnitude of benefit of adjuvant trastuzumab is similar for ILC and IDC.

Aromatase inhibitors or tamoxifen: is there a difference in these treatments for lobular tumors?

Little information is available about differences in the magnitude of benefit of hormonal therapy between ILC and IDC. In a retrospective analysis of a large series of invasive breast carcinomas with a long-term follow up, Rakha and colleagues studied 415 (8%) patients with pure ILC and 2901 (55.7%) with IDC, identified from a consecutive cohort of 5680 breast tumors [Rakha et al. 2008]. They found that in patients who received HT, those with ILC presented a better response to adjuvant hormonal therapy (HT), with improved survival relative to matched patients with IDC. However, whether the benefit from different endocrine therapies (i.e. tamoxifen or aromatase inhibitors [AIs]) differs by histologic subtype (i.e. ILC versus IDC) is unclear.

To assess the relative effectiveness of letrozole compared with tamoxifen for patients with IDC or ILC, Metzger-Filho and colleagues performed a retrospective analysis using data from the prospectively conducted phase III Breast International Group (BIG) 1–98 trial [Thurlimann et al. 2005; Metzger-Filho et al. 2015]. The BIG 1–98 was a four-arm study that compared 5 years of adjuvant monotherapy with the use of tamoxifen, 5 years with letrozole, or the two treatments administered sequentially, in postmenopausal women who have hormone receptor-positive early-stage BC; the retrospective analysis was limited to patients who were assigned to the monotherapy arms and whose tumors presented as centrally reviewed histology classified as IDC or classic ILC. Additionally, tumors were classified as luminal A (LA)-like or luminal B (LB)-like subtypes, according to immunohistochemistry surrogates: LA-like subtypes were ER or PgR positive, HER2 negative, and had a Ki-67 < 14%; LB-like subtypes were ER or PgR positive, HER2 negative, and had a Ki-67 ⩾ 14%. A total of 2923 patients who had early-stage BC (2599 with IDC and 324 with ILC) were analyzed, at a median follow up of 8.1 years. The percentages of LA-like and LB-like subtypes according to histology were 73.1% and 26.9%, respectively, for ILC; and 55.3% and 44.7%, respectively, for IDC. The size of ILC tumors was larger than for IDC tumors (ILC versus IDC size ⩾ 2 cm, 50% versus 34.8%), while nodal involvement was comparable between IDC and ILC. Treatment compliance, defined as completion of 5 years of treatment, was similar in the ILC and IDC subsets (67% and 71% of patients, respectively). Chemotherapy was administered before study initiation to 26.9% and 20.8% of patients with ILC and IDC, respectively. In multivariable models for DFS, the authors observed significant interactions between treatment and histology (ILC or IDC; p = 0.006), and treatment and subgroup (LB-like or LA-like; p < 0.01). Among patients diagnosed with ILC, significant reductions in the risk of DFS events in favor of letrozole compared to tamoxifen were seen in the subsets of LA-like (hazard ratio [HR], 0.50; 95% CI 0.32–0.78) or LB-like (HR, 0.34; 95% CI 0.21–0.55). By contrast, for patients diagnosed with IDC, the benefit in favor of letrozole was seen in the LB-like subset (HR, 0.65; 95% CI 0.53–0.79), but no difference was seen in the LA-like subset (HR, 0.95; 95% CI 0.76–1.20). In summary, the study showed that the magnitude of benefit of adjuvant letrozole varies by histologic subtype, and is greater for patients diagnosed with ILC versus IDC. These findings highlight the importance of identifying the molecular mechanisms of resistance to tamoxifen in luminal ILC.

Because of the retrospective nature of the above analysis and the reduced number of ILC occurrences, these results are not definitive, and there is a ave need for subsequent validation in larger data sets. In agreement with these data, results from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) VIII trial showed improved OS for patients with ILC who were treated with tamoxifen followed by anastrozole, versus those treated with tamoxifen monotherapy [Knauer et al. 2015]; however, additional results from BIG 1–98 failed to demonstrate similar results when tamoxifen therapy followed by letrozole was compared to tamoxifen monotherapy [Metzger-Filho et al. 2013a]. Although these data suggest that in clinical practice histologic subtype (i.e. ILC and IDC) should be considered in making the choice between using an AI versus tamoxifen as a therapy, it is important to note that these findings are derived from a retrospective analysis, and should be interpreted with caution.

In parallel to clinical studies, molecular studies have been conducted to understand the dif-ferential effectiveness of tamoxifen versus AI in treating ILC and IDC. Sikora and colleagues used ER-positive ILC cell lines (MM134 and SUM44PE) and xenografts, and observed that ER regulates a specific subset of genes in ILC compared with IDC [Sikora et al. 2014]. They also showed that MM134 cells exhibit de novo tamoxifen resistance and were induced to grow by hydroxytamoxifen acting as a partial agonist. Previous data also suggest that the expression of different forms of ERs, including the estrogen-related receptor γ [Riggins et al. 2008], as well as the persistence of ERβ expression [Huang et al. 2014] and fibroblast growth factor receptor signaling, might be related to tamoxifen resistance [Sikora et al. 2014].

Future perspectives

Recent studies have significantly contributed to the understanding of the landscape of somatic mutations in ILC. Cirello and colleagues performed a comprehensive analysis of 817 breast tumors samples (127 ILCs, 490 IDCs and 88 mixed IDC/ILCs) [Ciriello et al. 2015], and found that mutations targeting CDH1 (63% versus 2%), PIK3CA (48% versus 33%), RUNX1 (10% versus 3%), TBX3 (9% versus 2%), and FOXA1 (7% versus 2%) are more prevalent in ILCs relative to IDCs [Ciriello et al. 2015]. In contrast, the incidence of GATA3 mutations was found to be lower in ILCs compared with IDCs (5% in ILC versus 13% in IDC). Given that most ILCs are predominantly LA-like, and because some of these results could partly reflect genetic differences between ER-positive/luminal and ER-negative/basal-like BCs, the authors restricted their analysis to LA-like samples to better identify ILC discriminatory features. Their analysis confirmed a high incidence of CDH1, TBX3, and FOXA1 mutations in ILC, while the frequency of PIK3CA mutations in ILCs and IDCs was no longer significantly different. Additionally, GATA3 mutations (in 5% of ILCs versus 20% of IDCs) were the second most discerning event, following CDH1 mutations, and mutations in GATA3 were mutually exclusive with FOXA1 events. Finally, PTEN-inactivating alterations, including homozygous losses of the PTEN locus (10q23) and PTEN mutations, were the third most discriminating feature, between LA-like ILC and LA-like IDC (14% of ILC versus 3% of IDC).

In the second study, Desmedt and colleagues performed a comprehensive analysis of 417 ILC tumors [Desmedt et al. 2016]. The most relevant findings of this study were: (a) alterations in one of the three key genes of the PI3K pathway are present in more than half of the cases (PIK3CA, 43.3%; PTEN, 3.9%; and AKT1, 4.1%); (b) HER2 and HER3, respectively, are mutated in 5.1% and 3.6% of the tumors, respectively; and (c) mutations in FOXA1 and ESR1 copy number gains are detected in 9% and 25% of the samples, respectively. The authors used publicly available data from The Cancer Genome Atlas (TCGA), to conclude that all these alterations are more frequent in ILC than IDC. Interestingly, the subset classified as mixed, nonclassic ILC had an even higher prevalence of HER2 mutations (23.1%) and the solid subtype of ILC was enriched for ESR1 gains. Furthermore, the authors showed that chromosome 1q gains were associated with a better outcome, while 11p gains with a worse outcome, in terms of DFS. In addition, HER2 and AKT1 mutations were associated with increased risk of early recurrence. Taken together, these two studies clearly demonstrate that ILC has distinct genomic features when compared to IDC. Of importance, the different distribution of hotspot mutations in genes such as FOXA1 and GATA3 in ILC and IDC may have implications for disease biology and response to therapies. FOXA1 and GATA3 play key roles as ER transcriptional modulators and additional studies dedicated to understand the impact of these alterations are warranted [Carroll et al. 2005; Hurtado et al. 2011; Theodorou et al. 2013].

Conclusion

The distinct molecular portrait of ILC, along with different patterns of response to available systemic therapies, highlights the need for individualized therapies for patients diagnosed with ILC. Better tools are needed to identify the small fraction of patients that might benefit from chemotherapy and the molecular characterization of tumors can be useful in the allocation of patients to clinical trials. The role of FOXA1 and GATA3 genes in modulating the ER transcription program across ILC and IDC also deserves further attention. Finally, the differential effectiveness of AI when compared to tamoxifen for patients diagnosed with ILC needs to be validated in larger datasets.