Research Article

Pathological Response after Neoadjuvant Chemotherapy in Invasive Lobular Carcinoma

Saad Alqahtani1, Adher Alsayed2, Amal Alhefdhi3 and Osama Al Malik3*
1Department of Surgery, Majmaah University, Saudi Arabia
2Department of Medical Oncology, King Faisal Specialist Hospital & Research Centre, Saudi Arabia
3Department of General Surgery, King Faisal Specialist Hospital & Research Centre, Saudi Arabia


*Corresponding author: Osama Al Malik, Department of General Surgery, King Faisal Specialist Hospital & Research Centre, Riyadh 12713, Saudi Arabia


Published: 18 Dec, 2017
Cite this article as: Alqahtani S, Alsayed A, Alhefdhi A, Al Malik O. Pathological Response after Neoadjuvant Chemotherapy in Invasive Lobular Carcinoma. Clin Surg. 2017; 2: 1821.

Abstract

Introduction: Invasive Lobular Carcinoma (ILC) represents about 5% to 15% of all invasive breast cancers and has distinct clinico-pathological features and biological behavior. Neoadjuvant Chemotherapy (NACT) improves operability and increases the rates of Breast Conservative Surgery (BCS) by down-staging the tumor. The primary aim of this study was to assess the Pathological Complete Response (PCR) rates in ILC treated with NACT. Secondary aims included comparisons between ILC and Invasive Ductal Carcinoma (IDC) with regards to clinical response rates, rate of BCS, Disease-Free Survival (DFS) and Overall Survival (OS).
Methods: A retrospective case-control study included all cases with ILC treated at King Faisal Specialist Hospital & Research Centre (KFSH&RC) from 2002 to 2012 who received NACT and were compared to a control group with IDC in a 1:2 ILC/IDC ratio (ILC=31 vs. IDC =62 patients).
Results: ILC were slightly older and had higher hormone receptor positivity. There was no significant difference between the two groups with regards to menopausal status, clinical stage and the type of NACT. The Complete Clinical Response (CCR) rate (p=0.1) and the PCR rate (p=0.045) was higher in IDC compared to ILC. The mastectomy rate was higher in ILC compared to IDC (90.3% vs. 75.8%, respectively, p=0.04). The median follow up for this study was 40.5 months (range: 3 to 152). There was no difference in DFS among the two groups, but a higher OS was observed in the IDC group (p=0.02).
Conclusion: Similar to most reported studies, ILC is associated with lower CCR, PCR and BCS rates. ILC is associated with a worse long-term outcome despite a higher rate of estrogen-receptor positivity.
Keywords: Invasive lobular carcinoma; Invasive ductal carcinoma; Neoadjuvant chemotherapy; Pathological complete response

Introduction

Invasive Lobular Carcinoma (ILC) represents 5% to 15% of all breast cancers and a recent rise in its incidence has been reported [1-3]. It is more common in older patients and is characterized by larger tumors, higher Estrogen-Receptor (ER) positivity, Her2 negativity, lower histological grade and a higher frequency of bilateral disease [4,5]. Clinically, ILC is less likely to present with a distinct mass, frequently multifocal and often mammographically more occult, posing challenges in defining the extent of the disease [6]. The lower incidence, different clinico-pathological features and variable biological behavior all contribute to the evolving understanding of ILC and its most optimal management. Neoadjuvant Chemotherapy (NACT) is frequently used for locally advanced breast cancer to convert inoperable to operable disease and to achieve higher rates of Breast Conservative Surgery (BCS) [7,8]. In ILC, the Pathological Complete Response (PCR) rates after NACT is lower than in Invasive Ductal Carcinoma (IDC) (5.9% vs. 16.7%, respectively) [9] and additional surgeries are required after BCS in ILC to achieve negative margins [10,11]. On the other hand, other studies have shown improvement in BCS rates and similar re-surgery rates if controlled for tumor size in ILC [12,13]. We reviewed our experience of NACT in ILC with the aim to shed light on this controversial area and add to the knowledge and understanding of this less common but distinct type of invasive breast cancer.

Table 1

Another alt text

Table 1
Patient Demographics.

Table 1

Another alt text

Table 1
Patient Demographics.

Methods

In this retrospective study, 31 patients with non-metastatic ILC were compared to a matched group of 62 patients with IDC in a single institution. Patients with ILC treated between 2002 and 2012 were included as the study group. IDC treated during the same study period was used for comparison, using a 1:2 ratio of ILC/IDC. Patients in both groups were matched for year of diagnosis, clinical stage, NACT received prior to surgery and duration of follow up. The Breast Cancer Database at KFSH&RC was used as the main source of data. It prospectively records data about all breast cancer patients staged and treated at KFSH&RC. Data collected included patient, pathological and treatment characteristics. Missing variables were obtained from the patient's charts. This study was approved by the Institutional Review Board at KFSH&RC, Riyadh, Saudi Arabia. Patient’s characteristics were summarized using frequencies and percentages for categorical factors. Continuous variables were summarized using medians and ranges. Chi-Squared test was used to compare categorical variables among the study and the control group and Mann-Whitney test for the continuous variables. Probabilities of overall and disease-free survival were calculated using Kaplan- Meier estimator with variance estimated by Greenwood’s formula. Survival curves were compared using log-rank test. Multivariate analysis of factors associated with pathological response was done using the logistic regression model, while multivariate analysis of OS and DFS was done using proportional hazard regression models. Cancer type (ILC vs. IDC) was considered as a main effect in all models. All variables were tested for affirmation of the proportional hazard assumption. Factors that violate proportionality assumption were adjusted for through stratification. Stepwise model building approach was used in developing models for the different outcomes. Interactions between the main effect and other covariates had been tested. Statistical analysis was utilized using SPSS version 20.

Results

Forty cases of ILC were identified. Nine patients were excluded. Four had a mixed IDC with ILC in the final pathology. Two declined surgery after NACT. The other two had ILC on the biopsy, while the final pathology was IDC. One of the patients had missing pathological data. Thirty-one patient’s ILC were included and compared to a control group (62 patients with IDC). The median follow up was 40.5 (range: 3-152) months. Baseline characteristics are shown in Table 1. In both groups, all patients presented with Locally Advanced Breast Cancer (LABC). There was no difference between the two groups regarding menopausal status, clinical stage and the type of NACT (most of the patients received combined regimen Anthracycline and Taxanes, IDC 51.6%, ILC 45.2%). Patients with ILC were noted to have an older median age than IDC 47 (33-76) vs. 44.5 (33-65) and higher Estrogen Receptors (ER) and Progesterone Receptor (PR) positivity (74.2% vs. 48.4%). A 43 patients with IDC (69.4%) and 28 patients with ILC (90%) were Her2 negative. The mastectomy rate was 90.3% in ILC and 75.8% in IDC (p=0.04). The Clinical and Pathological Response rates are shown in Table 2. With regards to response, the clinical and pathological responses were higher with IDC compared to ILC. (p=0.045). In IDC, CCR was seen in 22 patients (35.5%) compared to 5 patients with ILC (16.1%). The PCR in the breast was higher in IDC (33.9%) compared to ILC (13%). Furthermore, the PCR in the axilla was higher in IDC (35.5%) compared to ILC (13%). None of the ILC achieved PCR in both breast and axilla while 15 (24.2%) cases of IDC achieved PCR in both breast and axilla.
Factors associated with PCR in the breast in univariate and multivariate analysis is shown in Table 3 and 4. Multivariate analysis showed that the hormone receptor status has significant impact on the PCR in the breast (OR 6.1, p=0.003) (Table 4). Higher PCR in IDC was related to ER (-) and PR (-) disease (p=0.002). Factors associated with PCR in the axilla in univariate and multivariate analysis is shown in Table 5 and 6. Univariate analysis showed that PCR in the axilla is higher in IDC compared to ILC (p=0.04). It was observed that; PCR is higher with stage II compared to those with stage III (p=0.03). Multivariate analysis confirmed a significant effect on PCR in the axilla in stage II compared to stage III (OR 0.3, p=0.04) (Table 6). There was no difference in DFS between the two groups (ILC and IDC) (Figure 1). OS was higher in the IDC group with long term follow-up (Figure 2).

Table 3

Another alt text

Table 3
Factors Associated With PCR in Breast (Univariate Analysis).

Table 4

Another alt text

Table 4
Factors Associated With PCR in Breast (Multivariate Analysis).

Table 5

Another alt text

Table 5
Factors associated with PCR in axilla (univariate analysis).

Table 6

Another alt text

Table 6
Factors Associated With PCR in Axilla (Multivariate Analysis).

Figure 1

Another alt text

Figure 1
Kaplan-Meier figure for DFS.

Discussion

Most of the data regarding the role of NACT in ILC have come from review of retrospective series and prospective studies are limited. These studies identified several differences in ILC compared to IDC in terms of response to NACT, surgical therapy and outcomes. NACT is given for down-staging and improving tumor resectability. PCR is considered a surrogate endpoint to predict DFS and OS in the neoadjuvant setting. In general, there is correlation between the response to NACT and survival, and a PCR after chemotherapy is an excellent prognostic predictor for overall survival [14]. It has been reported that ILC affects older women and is consistently associated with lower clinical and pathological response to NACT which is similar to our observation [15,16]. This accounts for the higher mastectomy rate associated with ILC in our experience and others [17,18]. Lower PCR can be partially explained by a higher expression of estrogen receptor positivity and Her2 negativity (Luminal A), a factor well known to be associated with lower PCR even with IDC histology [11,19], however other biological features could also contribute to this observation [20-22]. Hormone receptor positive tumors have good response to endocrine therapy and are less responsive to chemotherapy [13,23]. Dixon and associates reported more than 50% of their patients who were candidates at the beginning for mastectomy became suitable for BCS after receiving neoadjuvant Letrozole [23]. These finding have made some authors recommended neoadjuvant endocrine therapy in patients with ILC [13,23,24]. On the other hand, some authors still advocate NACT if breast conservation is desired as this approach is associated with a high BCS rates [25]. In contrast to our study most studies have reported a similar or better long term outcome for ILC compared to IDC [11,26,27]. On the other hand, we have found a worse overall survival. In few studies with longer follow-up, worse survival outcomes were reported similar to our study [28,29]. This indicates that late recurrences are not uncommon with ILC. In addition, our patients presented with locally advanced breast cancer, a factor may explain the worse overall survival. It is likely that ILC is molecularly distinct from IDC and only prospective studies will answer the many controversies associated with this less common distinct type of breast cancer [30].

Figure 2

Another alt text

Figure 2
Kaplan-Meier figure for OS.

Conclusion

In conclusion, ILC are less responsive to NACT and are associated with higher mastectomy rates. It is molecularly distinct from IDC and may have a worse long term outcome. We acknowledge that there are limitations in our study, the retrospective nature and the small number of patients involved. However, it is important to consider these differences and attempt to address the management of this second most common type of breast cancer in prospective multicenter studies as this will improve our understanding and resolve many controversies associated with this disease.

Acknowledgment

We would like to thank Ms. Tusneem A. Elhassan, MSc, (Biostatistician) & Ms. Romelia P. Retuta (Clinical Research Coordinator, Breast Cancer Program Section), Department of Oncology, King Faisal Specialist Hospital and Research Center for their efforts.

References

  1. Anderson JA. Invasive breast carcinoma with lobular involvement. Frequency and location of lobular carcinoma in situ. Acta Pathol Microbiol Scand A. 1974;82(6):719-29.
  2. Verkooijen HM, Fioretta G, Vlastos G, Morabia A, Schubert H, Sappino AP, et al. Important increase of invasive lobular breast cancer incidence in Geneva, Switzerland. Int J Cancer. 2003;104(6):778-81.
  3. Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289(11):1421-4.
  4. Arpino G, Bardou VJ, Clark GM, Elledge RM. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 2004;6(3):R149-56.
  5. Rakha EA, El-Sayed ME, Menon S, Green AR, Lee AH, Ellis IO. Histologic grading is an independent prognostic factor in invasive lobular carcinoma of the breast. Breast Cancer Res Treat. 2008;111(1):121-7.
  6. Kim SH, Cha ES, Park CS, Kang BJ, Whang IY, Lee AW, et al. Imaging features of invasive lobular carcinoma: comparison with invasive ductal carcinoma. Jpn J Radiol. 2011;29(7):475-82.
  7. Mamounas EP. NSABP Protocol B-27. Preoperative doxorubicin plus cyclophosphamide followed by preoperative or postoperative docetaxel. Oncology. 1997;11(6):37-40.
  8. Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15(7):2483-93.
  9. Petrelli F, Barni S. Response to neoadjuvant chemotherapy in ductal compared to lobular carcinoma of the breast: a meta-analysis of published trials including 1,764 lobular breast cancer. Breast Cancer Res Treat. 2013;142(2):227-35.
  10. Wenzel C, Bartsch R, Hussian D, Pluschnig U, Altorjai G, Zielinski CC, et al. Invasive ductal carcinoma and invasive lobular carcinoma of breast differ in response following neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF. Breast Cancer Res Treat. 2007;104(1):109-14.
  11. Cristofanilli M, Gonzalez-Angulo A, Sneige N, Kau SW, Broglio K, Theriault RL, et al. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol. 2005;23(1):41-8.
  12. Morrow M, Keeney K, Scholtens D, Wei J, Steel J, Khan SA. Selecting patients for breast-conserving therapy: the importance of lobular histology. Cancer. 2006;106(12):2563-8.
  13. Boughey JC, Wagner J, Garrett BJ, Harker L, Middleton LP, Babiera GV, et al. Neoadjuvant chemotherapy in invasive lobular carcinoma may not improve rates of breast conservation. Ann Surg Oncol. 2009;16(6):1606-11.
  14. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-804.
  15. Fu L, Tsuchiya S, Matsuyama I, Ishii K. Clinicopathologic features and incidence of invasive lobular carcinoma in Japanese women. Pathol Int. 1998;48(5):348-54.
  16. Hanagiri T, Nozoe T, Mizukami M, Ichiki Y, Sugaya M, Yasuda M, et al. Clinicopathological characteristics of invasive lobular carcinoma of the breast. Asian J Surg. 2009;32(2):76-80.
  17. Cocquyt VF, Blondeel PN, Depypere HT, Praet MM, Schelfhout VR, Silva OE, et al. Different responses to preoperative chemotherapy for invasive lobular and invasive ductal breast carcinoma. Eur J Surg Oncol. 2003;29(4):361-7.
  18. Anwar IF, Down SK, Rizvi S, Farooq N, Burger A, Morgan A, et al. Invasive lobular carcinoma of the breast: should this be regarded as a chronic disease? Int J Surg. 2010;8(5):346-52.
  19. Zhu MZ, Yu XF, He XM, Feng WL, Fan JH, Li J, et al. Clinicopathological features of invasive lobular carcinoma of the breast: A nationwide multicenter study in China. J Cancer Res Ther. 2015;11:C89-94.
  20. Domagala W, Markiewski M, Kubiak R, Bartkowiak J, Osborn M. Immunohistochemical profile of invasive lobular carcinoma of the breast: predominantly vimentin and p53 protein negative, cathepsin D and oestrogen receptor positive. Virchows Arch A Pathol Anat Histopathol. 1993;423(6):497-502.
  21. Koo JS, Jung W. Clinicopathlogic and immunohistochemical characteristics of triple negative invasive lobular carcinoma. Yonsei Med J. 2011;52(1):89-97.
  22. Lips EH, Mukhtar RA, Yau C, de Ronde JJ, Livasy C, Carey LA, et al. Lobular histology and response to neoadjuvant chemotherapy in invasive breast cancer. Breast Cancer Res Treat. 2012;136(1):35-43.
  23. Dixon JM, Renshaw L, Dixon J, Thomas J. Invasive lobular carcinoma: response to neoadjuvant letrozole therapy. Breast Cancer Res Treat. 2011;130(3):871-7.
  24. Narbe U, Bendahl PO, Grabau D, Rydén L, Ingvar C, Fernö M. Invasive lobular carcinoma of the breast: long-term prognostic value of Ki67 and histological grade, alone and in combination with estrogen receptor. Springerplus. 2014;3:70.
  25. Bollet MA, Savignoni A, Pierga JY, Lae M, Fourchotte V, Kirova YM, et al. High rates of breast conservation for large ductal and lobular invasive carcinomas combining multimodality strategies. Br J Cancer. 2008;98(4):734-41.
  26. Garcia-Fernandez A, Lain JM, Chabrera C, Garcia Font M, Fraile M, Barco I, et al. Comparative Long-term Study of a Large Series of Patients with Invasive Ductal Carcinoma and Invasive Lobular Carcinoma. Loco-Regional Recurrence, Metastasis, and Survival. Breast J. 2015;21(5):533-7.
  27. Lim ST, Yu JH, Park HK, Moon BI, Ko BK, Suh YJ. A comparison of the clinical outcomes of patients with invasive lobular carcinoma and invasive ductal carcinoma of the breast according to molecular subtype in a Korean population. World J Surg Oncol. 2014;12:56.
  28. McCart Reed AE, Kutasovic JR, Lakhani SR, Simpson PT. Invasive lobular carcinoma of the breast: morphology, biomarkers and 'omics. Breast Cancer Res. 2015;17:12.
  29. Rakha EA, El-Sayed ME, Powe DG, Green AR, Habashy H, Grainge MJ, et al. Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. Eur J Cancer. 2008;44(1):73-83.
  30. Gruel N, Lucchesi C, Raynal V, Rodrigues MJ, Pierron G, Goudefroye R, et al. Lobular invasive carcinoma of the breast is a molecular entity distinct from luminal invasive ductal carcinoma. Eur J Cancer. 2010;46(13):2399-407.