|Ahead of print publication
Pattern of local recurrence and metastasis in carcinoma breast according to molecular subtype in patients treated with definitive intent
Samantha Adriana Dsouza, Sandesh B Rao, Donald J Fernandes, Sharaschandra Shankar, MS Vidyasagar, Sheeba Santmayer
Department of Radiation Oncology, Father Muller Medical College Hospital, Mangalore, Karnataka, India
|Date of Submission||04-Jan-2022|
|Date of Decision||05-Feb-2022|
|Date of Acceptance||10-Mar-2022|
|Date of Web Publication||24-Aug-2022|
Sandesh B Rao,
Department of Radiation Oncology, Father Muller Medical College Hospital, Mangalore, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Despite the advances in breast cancer treatment, it has a higher rate of mortality. The response of treatment varies significantly; this could be due to the various subtypes that determine the course of the disease. In this study, we evaluated patients who were treated definitively and had developed organ-specific metastasis and local recurrence according to biological subtype. Materials and Methods: Out of 856 patients who were diagnosed to have carcinoma breast from the year January 2015 to January 2020, 468 patients were treated definitively, out of which 55 patients developed recurrent or metastatic disease after completion of treatment. Results: The most frequent subgroup for relapse was triple-negative breast cancer (TNBC) 23 (41.8%). Twenty-two (40%) had multiple metastases at the time of first distant recurrence. The most common site of distant recurrence was bone 28 patients (50.9%) with maximum incidence in Luminal B subgroup (23.6%), followed by liver metastasis 23 patients (41.81%) with the highest incidence seen among TNBC (18%), followed by lung 19 (34.5%) patients with maximum incidence in TNBC (16.3%) followed by brain 5 (9%) patients. Locoregional recurrence was observed in 13 patients, out of which 8 (61.5%) patients had TNBC molecular subgroup. Conclusion: Our results demonstrate an association between molecular subtype and pattern of recurrence.
Keywords: Molecular subtype, recurrence, relapse
|How to cite this URL:|
Dsouza SA, Rao SB, Fernandes DJ, Shankar S, Vidyasagar M S, Santmayer S. Pattern of local recurrence and metastasis in carcinoma breast according to molecular subtype in patients treated with definitive intent. J Radiat Cancer Res [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.journalrcr.org/preprintarticle.asp?id=354435
| Introduction|| |
Breast cancer is the major cause of cancer in women worldwide, accounting for approximately 2.30 million new cases in 2020, that represents approximately 11.7% of all cancer cases. With over 6,850,000 deaths, it is the fifth leading cause of cancer death worldwide. Breast cancer accounts for around 26.3% of all cancers among women in India and has been on the rise for the past decade.,
Breast cancer is known to be a heterogeneous disease; this could be owed to the fact that it has a wide range of phenotypical variants which have been linked to different molecular subtypes. A multimodality strategy is required for the treatment of breast cancer which includes surgery (either breast-conserving surgery or modified radical mastectomy), chemotherapy (either neoadjuvant or adjuvant), depending on the stage at the time of diagnosis, radiotherapy as indicated, and hormone therapy depending on the receptor status and menstrual status. Treatment decision for every patient is determined by several factors such as tumor morphology, grade, and size, presence of lymph node metastasis, and hormone receptor status. Despite the advancements in breast cancer treatment, the mortality rate is higher. Treatment response varies greatly, which could be attributed to the many subtypes that influence the disease's course.
Breast cancer has at least four subtypes. Luminal A (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive, HER2 negative, Ki-67 – <14%), Luminal B (ER positive and/or PR positive, HER2 negative, Ki-67 – >14% or ER positive and/or PR positive, HER2 positive, Ki-67 – any), HER2 enriched (ER negative, PR negative, HER2 positive, Ki-67 – any), and basal type (ER negative, PR negative, HER2 negative, Ki-67 – any). Gene expression profiling revealed that the best cutoff for Ki67 to discriminate between Luminal A and Luminal B breast cancer was 14. Luminal A subtype is associated with better prognosis, whereas the basal cell subtype is aggressive nature of disease hence associated with poor prognosis. Although the specific definitions of these subtypes are still being debated, it is evident that they can be replicated in several unrelated data sets and that their prognostic significance has been established in these settings.
In this study, we looked at the ER, PR, and human epidermal growth factor receptor 2 (HER2) status of patients who had been treated definitively and had developed organ-specific metastases and local recurrence.
The aim of this study was to establish a possible association between various molecular subtypes and pattern of local recurrence and distant metastasis among patients treated with a definitive intent.
| Materials and Methods|| |
This was an observational descriptive record-based study on patients diagnosed with female breast cancer and was treated definitively from January 2015 to January 2020 at our hospital. These patients were analyzed for local recurrence and distant metastasis.
Out of 856 patients who were diagnosed to have carcinoma breast from the year January 2015 to January 2020, 162 patients were diagnosed with metastatic disease on initial assessment and 108 patients had received definitive treatment from other hospitals. A total of 586 patients were treated with a definitive intent, out of which 118 patients were lost to follow-up. Out of the 468 patients analyzed, 55 patients developed recurrent or metastatic disease after completion of definitive treatment. Clinical, pathological, and treatment characteristics were noted, as mentioned in [Table 1].
Pathological assessment was done based on immunohistochemistry (IHC) profile as Luminal A, Luminal B, HER2 enriched, and basal type. ER and PR status was considered positive if staining was ≥1%. HER2 expression was determined by IHC. IHC of 3+ was considered HER2-positive expression, whereas IHC of 0 or 1+ was considered HER2-negative expression. When IHC of 2+ was noted, an additional test was done by fluorescence in situ hybridization, and an amplification ratio of ≥2 was considered HER2 overexpression.
Parameters such as age, stage of the disease, grade and histology, hormone receptor status, type of surgery, chemotherapy, trastuzumab/hormonal therapy received, and radiation therapy were taken into account [Table 1]. The primary outcome was to compare the patterns of relapse of different breast cancer subtypes. The recurrence was classified as local, regional, and distant. Local recurrence included the recurrence in ipsilateral breast and chest wall. Regional recurrence included recurrence at regional lymph nodes. Distant recurrences consisted of distant lymph node metastases, brain, liver, bone including bone marrow, lung including pleura, and other sites such as but not limited to spleen, peritoneum, and other organs.
The data were analyzed statistically using descriptive statistics, namely mean, standard deviation, and percentage whenever applicable. Appropriate parametric and nonparametric tests such as independent sample, t-test, Chi-square test, and Fisher's exact test were done. The data were entered into MS Excel, and statistical analysis was performed using IBM SPSS Statistics 2®.
| Results|| |
A total of 55 eligible patients were included in the study. 4 (7.27%) patients were in Luminal A, 18 (32.72%) patients were in Luminal B, 10 (18.18%) patients were in HER2 enriched, and 23 (41.8%) patients were in triple-negative breast cancer (TNBC) subgroups, as depicted in [Figure 1].
Clinical, pathological, and treatment characteristics and their distribution among various subgroups are listed in [Table 1]. The median age across the subgroups was 49 (27–86) at the time of diagnosis. Among them, patients with TNBC were from a younger age group.
Invasive ductal carcinoma was the most common histological type and was seen maximum in TNBC group 22 patients (40%). The most common grade across all subgroups was Grade 3 (49%). Fifteen (27%) patients in TNBC group had the maximum number of patients. Across all subgroups, T2 tumor stage was seen at a higher rate (41.81%) with maximum number 10 (18.18%) patients in TNBC arm. The most common nodal status was N2 (32.72%) with maximum number of patients from Luminal B subgroup.
Across all the subgroups, majority (94.5%) of the patients had undergone Modified Radical Mastectomy (MRM) as the surgical treatment modality. Sixty-three percent of the patients received adjuvant chemotherapy and 33% of the patients received neoadjuvant chemotherapy. 92.7% of all patients received adjuvant radiation therapy. All the patients with hormonal receptor-positive status were on hormonal therapy. Only 2 (3.8%) patients among the HER2-enriched arm had received trastuzumab.
During follow-up, locoregional and distant recurrence was seen in 4 (7.27%) patients in Luminal A, 18 (32.72%) patients in Luminal B, 10 (18.18%) in HER2 enriched, and 23 (41.81%) patients in TNBC. Among the 55 relapsed patients, 22 (40%) had multiple metastases at the time of first distant recurrence.
The most common site of distant recurrence was bone 28 patients (50.9%) with maximum incidence in Luminal B subgroup (23.6%), followed by liver metastasis 23 patients (41.81%) with the highest incidence seen among TNBC (18%), lung 19 (34.5%) patients with maximum incidence in TNBC (16.3%), and brain 5 (9%) patients. Other distant sites of metastasis were spleen seen in 1 patient with Luminal B subgroup and epigastric nodes seen in 1 patient with TNBC subgroup, as depicted in [Figure 1].
Locoregional recurrence was observed in 13 patients, out of which 8 (61.5%) patients had TNBC molecular subgroup, as depicted in [Figure 2].
The relationship between molecular subtype and site of recurrence is evaluated in [Table 2].
| Discussion|| |
Malignant cells' natural behavior is invasion and metastasis. The pattern of metastasis is a complicated mechanism that is yet poorly understood. Many prior studies have found that molecular subtypes play a role in defining the severity of the disease and how well it responds to treatment.,,, Only a few studies have looked at the link between molecular subtype and metastatic disease.,,,, Molecular subtypes play a significant impact in the progression of the disease, such as local recurrence or metastasis.
This research shows a pattern and recurrence based on molecular subtype. Despite the fact that our study was retrospective, all of the patients were treated according to NCCN guidelines. Seventy-two percent of the patients in this study were above 40 years of age. Sixty-two percent of the patients had tumor stage between T0–T2 and 27% of the patients had node-negative disease. Forty-nine percent of the patients had Grade 3 disease, with most of the patients across all arms having invasive ductal carcinoma as the histology. In literature, chemotherapy usage was 23.9%–98.3% in Luminal A, 36.8%–97.1% in Luminal B, 53.4%–100% in HER2 overexpressing, and 48%–96.7% in basal type. In our study, this value was 50%, 61%, 50%, and 78%, respectively.
According to Wu et al., the Luminal A subtype has a low rate of local and distant recurrence, whereas the triple-negative and HER2-enriched subtypes have a greater probability of both local and distant recurrence. TNBC was shown to have the highest rate of locoregional recurrence, all of which were consistent with our findings.
Bone metastasis was the most common site of distant metastasis in patients with the Luminal subtype in prior investigations,,,,14],, which was also confirmed in our study. There were a total of 28 patients with bone metastases, 13 (46.4%) of whom were from the Luminal B subgroup.
When compared to Luminal subgroups, TNBC and HER2-enriched subgroups had increased frequency of brain metastasis.,, In our study, TNBC had the highest rate of brain metastasis in our investigation.
According to Chalil et al. and a number of other studies, lung metastasis was more prevalent in TNBC patients.,,, This was similar to our cohort. The hazard risk of lung metastasis in TNBC is almost seven-fold higher than Luminal A subgroup.
TNBC and HER2-enriched subgroups were more likely to develop brain metastases.,,, The majority of the brain metastasis patients in our study were from the TNBC and HER2-enriched subgroups. When compared to the Luminal A subtype, the incidence of brain metastases is 21.9- and 18.0-fold higher in HER2 enriched and TNBC, respectively.
| Conclusion|| |
Our results demonstrate a significant association between molecular subtype and pattern of recurrence. Further large trials are required to tailor treatment based on molecular subtypes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al
. Molecular portraits of human breast tumours. Nature 2000;406:747-52.
Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al.
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-74.
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al.
Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009;101:736-50.
Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al.
Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006;295:2492-502.
Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, et al.
Basal-like and triple-negative breast cancers: A critical review with an emphasis on the implications for pathologists and oncologists. Mod Pathol 2011;24:157-67.
Ignatov T, Eggemann H, Burger E, Costa SD, Ignatov A. Hormone receptor status does not alter the effect of trastuzumab in breast cancer. Endocr Relat Cancer 2016;23:349-55.
Kim SI, Sohn J, Koo JS, Park SH, Park HS, Park BW. Molecular subtypes and tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Oncology 2010;79:324-30.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al.
Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418-23.
Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al.
Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008;68:3108-14.
Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al.
Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271-7.
Metzger-Filho O, Sun Z, Viale G, Price KN, Crivellari D, Snyder RD, et al.
Patterns of Recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: Results from international breast cancer study group trials VIII and IX. J Clin Oncol 2013;31:3083-90.
Sihto H, Lundin J, Lundin M, Lehtimäki T, Ristimäki A, Holli K, et al.
Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: A nationwide cohort study. Breast Cancer Res 2011;13:R87.
Park HS, Kim S, Kim K, Yoo H, Chae BJ, Bae JS, et al.
Pattern of distant recurrence according to the molecular subtypes in Korean women with breast cancer. World J Surg Oncol 2012;10:4.
Chalil N, Nair IP, Aliyarukunju N, Latheef A. A cross-sectional study on the pattern of recurrence in carcinoma breast patients based on molecular subtypes. Int Surg J 2020;7:1712-7.
Wu X, Baig A, Kasymjanova G, Kafi K, Holcroft C, Mekouar H, et al.
Pattern of local recurrence and distant metastasis in breast cancer by molecular subtype. Cureus 2016;8:e924.
Kaplan MA, Arslan UY, Işıkdogan A, Dane F, Oksuzoglu B, Inanc M, et al
. Biological subtypes and distant relapse pattern in breast cancer patients after curative surgery (study of Anatolian society of medical oncology). Breast Care (Basel) 2016;11:248-52.
[Figure 1], [Figure 2]
[Table 1], [Table 2]