Occult Breast Cancer in High-Risk Gene-Positive Pakistani Women Undergoing Contralateral Prophylactic Mastectomy/Prophylactic Mastectomy: Implications for Sentinel Lymph Node Biopsy

Abstract

Introduction:

Sentinel lymph node biopsy (SLNB) of the axilla is standard in breast cancer (BC) management; however, its role in prophylactic/contralateral prophylactic mastectomy (CPM) is still questioned. To avoid future consequences on surgical morbidity and socioeconomic aspects in low and middle-income countries (LMICs), we intend to determine the prevalence of occult breast cancer (OBC) among CPM cases.

Objective:

To determine the prevalence of OBC in patients undergoing prophylactic mastectomy (PM).

Design:

This is a retrospective cohort study.

Materials and methods:

This retrospective cohort study is conducted at a tertiary-care hospital from January 2017 to December 2022. All individuals with the positive genetic test for high-risk breast cancer (HRBC) genes who underwent PMs/CPM at our centre were included. We analysed data using SPSS version 23.0.

Results:

Twenty-six mutation-positive females underwent PM/CPM (16.1%). Two (7.69%) of 26 had later post-PM recurrence. Only 8 (30.76%) patients had SLNB and all were negative. No OBC was seen in PM/CPM specimens, whereas 3 (11.5%) had atypical ductal hyperplasia (ADH). Two of the ADH had BI-RADS-1, whereas 1 was BI-RADS-4 (33.3%) on the preoperative assessment. Results also showed that with an increase in the tumour grade of the diseased breast, the BI-RADS score of the asymptomatic breast was subsequently increased (P = .029).

Conclusion:

Our study shows negative OBCs in PM/CPM cases with persistently negative SLNB results; however, ADH is identified in 11.5% of specimens. Our results suggest that SLNB can be safely omitted in patients undergoing CPM, but, preoperatively, patient and disease factors should be considered.

Introduction

Recent studies have reported the rising incidence of high-risk breast cancer (HRBC) genes among Pakistani women, with a concomitant increase in referrals for prophylactic mastectomies(PMs) seen across different centres in the country. ¹ The HRBC genes are linked to hereditary breast cancers (BC) which contribute to an overall 5% to 10% of BC cases. ² The main identified HRBC genes contributing to the development of BCs are BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53, ATM, BARD1, CHEK2, NF1, RAD51C/D, and STK11. Among these culprit genes, BRCA1/2 contribute to most hereditary BC cases with an absolute risk of BC development of ⩾60%.^2,3

The role of sentinel lymph node biopsy (SLNB) among patients with BC is well established; however, we lack data regarding the role of SLNB for patients who are undergoing surgery for prophylactic reasons without proven malignancies. ⁴ Literature has reported an occult breast cancer (OBC) rate of 0% to 11.3% among PM specimens.^4,5 Most malignant lesions in PM specimens are found to be in situ, allowing exemption from axillary staging. However, if OBC is detected, axillary management is recommended. ⁶ Albeit SLNB has associated complications, that is, postoperative pain, lymphedema, paresthesia, infections, and rare reactions to the injected dye. ⁷ However, in low and middle-income countries (LMICs), financial factors are one of the biggest challenges when it comes to SLNB. Therefore, the question persists regarding skipping SLNB among patients undergoing PMs or contralateral prophylactic mastectomies (CPMs). However, before standardising the practice in our population, we need convincing evidence that the frequency of OBC is low among our patients. Identifying the true frequency of OBC in our HRBC gene–positive patients undergoing PM could allow us to skip SLNB, reducing both the psychological impact and financial burden on patients and families. Furthermore, the socioeconomic status of our population has also declined over the last few years due to the economic crises faced worldwide, with more pronounced aftereffects seen in LMICs like Pakistan. ⁸

Keeping in view the financial perspective as an added procedure in PM/CPM cases along with added morbidity to the axilla, our primary aim of this study is to evaluate the frequency of OBC among patients who underwent PMs for their HRBC gene positivity, with the endpoint that SLNB can be safely omitted in PM cases. Our secondary goal is to correlate the radiological findings with final histopathological results among OBC-positive patients and to see the histopathological pattern in PM specimens.

Materials and Methods

This is a single-centre, retrospective cohort study, conducted in the section of Breast Surgery, Aga Khan University Hospital, Karachi. We used nonprobability consecutive sampling and included cases from January 2017 till December 2022, who presented to breast surgery clinics for PM/CPM after their positive genetic test results. The associated data are deposited at clinicaltrials.gov: NCT05771454.

Ethics approval

All relevant methods were performed according to the ‘Declaration of Helsinki’. The study was conducted after clearance from the Ethical Review Committee of our institute: ERC number: 2022-8048-23560.

Data collection

Before inclusion in the study, verbally informed consent was taken for telephonic interviews, and the demographic information along with the genetic and type of surgery availed was gathered on a proforma (Supplement 1). Genetic testing was done on all those patients who qualified for the National Comprehensive Cancer Network (NCCN) genetic testing criteria. ⁹ Information regarding disease characteristics, radiology, and histopathological specifications were gathered from the hospital repository. All individuals with the positive genetic test for HRBC genes who underwent PM/CPMs at our centre at the time of initial BC treatment or later after BC treatment, as well as carriers, were included in the study. We excluded individuals who did not consent to give interviews and those who had bilateral BCs at the time of diagnosis. For radiological assessment and categorisation of mammograms, ultrasounds, and magnetic resonance imaging (MRIs), we used the American College of Radiologists Breast Imaging Reporting and Data System (BI-RADS).^10,11 For deciding qualification regarding SLNB among PM/CPM cases, we used a BI-RADS score of ⩾ 2 of the normal breast and clinical suspicion of the operating surgeon for OBC diagnosis before surgery. Histopathology was considered a gold standard for confirming the presence/absence of OBCs on PM/CPM specimens. To keep the bias minimal, only 1 interviewer collected the data via phone calls.

Statistical analysis

SPSS 23.0 was used to examine the data. Qualitative variables were expressed in frequencies and percentages (eg, gender, family history), whereas continuous variables like age were presented as median with range (interquartile range; IQR). The Pearson chi-square and Fisher exact tests were used to analyse categorical variables. Using a 95% confidence interval, a P value of .05 or lower was deemed significant.

Results

Of 498 eligible individuals referred for genetic testing at our centre, 161 individuals tested positive for HRBC genes (32.32%). Of all positive female patients, only 26 underwent PM/CPM (16.1%) and the spectrum of genetic mutations among them is demonstrated in Figure 1.

Figure 1.

Spectrum of high-risk breast cancer (HRBS) genes in women underwent prophylactic mastectomy (PM).

Around 14 of 26 (69.2%) had a positive family history with their first-degree relatives affected. The median age to avail PM/CPM in our cohort was 35 years with an age range of 27 to 63 years (IQR = 13). The procedures undertaken for affected breasts were modified radical mastectomy in 14 of 22 (63.6%), followed by mastectomy + SLNB in 7 of 22 (31.8%), whereas 1 patient (4.5%) had breast-conserving surgery (BCT). Only 4 of 26 women were carriers (15.3%) among females who had a PM. Regarding prophylactic surgery, 21 (80.76%) opted for CPM, 5 (19.23%) opted for bilateral prophylactic mastectomy (BPM), 4 of 5 who had BPM were carriers, whereas 1 had initially BCT at the time of BC diagnosis and later opted for BPM as per her genetics result. However, 2 of 26 (7.69%) of them all had recurrent diseases as distant metastasis due to the initial stage of BC diagnosis; both were stage III at the time of initial diagnosis, <40 years old, having a positive family history, oestrogen/progesterone, and human epidermal growth factor receptor-2 neu negative, whereas among all carriers with BPM, no cancer diagnosis was reported until now.

Our majority of patients had stage II disease of the affected breast at the time of diagnosis, that is, 10 of 26 (38.46%), followed by stage III in 9 of 26 (34.6%) patients, whereas 3 had stage I disease (11.5%). The most common histopathological type identified in the diseased breast was invasive ductal carcinoma (IDC); 19 of 22 (86.3%), which was prevalent more in BRCA1 patients; 15 of 22 (68%), followed by BRCA2; 4 of 22 (18%). Invasive lobular carcinoma (ILC) was identified in only 1 patient (4.5%) and was associated with BRCA2. Similarly, metaplastic carcinoma was identified in 2 of 22 BC specimens (9.09%) and was equally distributed among BRCA1/2 patients. Most BCs were grade 3 when diagnosed, that is, 12 of 22 (54.5%), followed by grade 2, 10 of 22 (45.45%). Overall, 10 of 22 patients received neo-adjuvant chemotherapy (NACT) for BC and pathological complete response (PCR) was achieved in 8 of 10 (80%) of patients. In comparison, 2 patients had a pathological partial response after NACT, that is, 20% (P < .001). Our results could not show any statistically significant correlation between NACT response and different genetic variations of the patients (P = .187). The demographic and clinical characteristics of patients with BC who underwent PM/CPM are shown in Table 1.

Table 1.

Demographic and clinical characteristics of patients with breast cancer undergoing PM/CPM.

S. no.	Characteristics	Groups	N	%	P value
	BC stage at diagnosis	Stage I	3	11.5	—
		Stage II	10	38.5
		Stage III	9	34.6
	Histopathology of diseased breast	IDC	19	86.4	—
		ILC	1	4.5
		Metaplastic carcinoma	2	9.1
	Grade at diagnosis	Grade 2	10	45.5
		Grade 3	12	54.5
	NACT response	PCR	8/10	80	<.001
		PPR	2/10	20
	SLNB in PM/CPM group	Negative	8/8	100	<.001
	Atypical lesions in nondiseased breast	ADH	2	7.7	—
		ADH + FEA	1	3.8

Among the PM/CPM group, only 8 of 26 (30.76%) had SLNB and all were negative for any lymph node metastasis (P = <.001). In this subset, SLNB was guided by factors such as clinical suspicion, BC status of contralateral diseased breast at the time of surgery (in CPM cases), elevated BI-RADS scores on normal breast (in CPM cases), and the presence of atypical ductal hyperplasia (ADH) identified preoperatively. We were not able to identify invasive focus/OBC in PM/CPM specimens; however, 3 of 26 (11.5%) of PM/CPM specimens had ADH on histopathology. Two of the ADH cases had a BI-RADS-1 score, whereas 1 ADH case was reported as BI-RADS-4 (33.3%) on the preoperative radiological assessment. Only 1 of 3 patients with ADH had SLNB and it was negative for metastasis (P = .67). Two of 3 (66.6%) patients with ADH had metaplastic BC of diseased breasts with associated grade 3, whereas 1 patient had IDC grade 2. Of these 3 patients, only 1 patient received NACT for contralateral BC treatment, whereas 2 had upfront surgery for a diseased breast along with CPM. No treatment responses on CPMs were identified on histopathology among patients who received NACT.

The distribution of patients in different BI-RADS score categories on the preoperative assessment using mammograms and ultrasound before the PM/CPM is represented in Table 2. As anticipated, only 2 of our patients had preoperative MRIs as a part of their assessment protocol and both were BI-RADS-2 (7.69%). The high cost of MRI was the main reason for using mammogram/ultrasound as an alternative to the recommended modality for preoperative assessment. Results also showed that with an increase in the tumour grade of diseased breasts, the BI-RADS score of asymptomatic breasts was subsequently increased from BI-RADS-1 to BI-RAD-4 (P = .029). Similarly, 33.3% of PM patients with ADH had a BI-RADS-IV score on preoperative imaging.

Table 2.

BI-RADS scores before prophylactic mastectomy on preoperative imaging.

S. no.	BI-RADS score	No. of patients (n = 26)	Percentage
1	BI-RADS-0	2	7.69
2	BI-RADS-1	13	50
3	BI-RADS-2	5	19.2
4	BI-RADS-3	4	15.3
5	BI-RADS-4	2	7.69

Discussion

Limited data were available from our region due to lack of genetic testing, loss of follow-up, and lack of PM. ¹ In our study, 161 (32.32%) individuals tested positive for high-risk BC genes, and comparable to studies from adjacent countries, most these patients were BRCA1-positive (69.2%), followed by BRCA2-positive (19.23%) and other high-risk genes.^12,13 Only 26 (16.1%) of our patients chose PM/CPM, which is in line with the poor adoption of PM/CPM in other LMICs in the area.^12,13 Both studies reported recurrence among those who declined PM, but only one of them found a patient with regional recurrence following PM. In contrast, we identified 2 cases of recurrence among those who had received CPM originally (7.69%); however, they had distant recurrence which may correspond with the initial stage of BC diagnosis.^12,13 This recurrence rate is still lower than in cases that do not receive a PM, reiterating PM’s status as the gold-standard procedure for carriers with enhanced survival benefits.^{13 -15} In contrast, PM tends to be more prevalent in high-income countries (HICs) than in LMICs, which is attributed to variables such as cost apprehension, social stigma, family pressure, a lack of health care resources, and a lack of PM education and counselling in LMICs.^{15 -17}

Our study showed that most patients had stage 2 (38.6%) BC at the time of CPM, with the most common histopathological type as IDC in 86.3%, and most patients being grade II/III, these results are consistent with the study from China. ¹² We identified ILC in 1 specimen (4.5%) and it was present in a BRCA2 patient, which is in contrast to another study where half of their BRCA1/2 cohort had ILC on histopathology. ¹⁸ A similar study correlated ILC with CDH1 and BRCA2 mutations, respectively, and showed no correlation of ILC to BRCA. ¹⁹ We identified metaplastic carcinoma in 9.09% of cases and it was distributed equally in both BRCA1/2 genes. A study identified 30.7% of metaplastic carcinomas to be associated with BRCA1; however, it is difficult to make an inference from our results because of very few metaplastic cases. ²⁰ Overall, 80% of our patients showed PCR after NACT which is close to the results published from India for BRCA patients, that is, 66.7%. ¹⁶

Regarding CPM, literature has persistently shown a lower rate of OBC identification in PM specimens, which correlates with our results where no OBC was identified.^4,5 Like our results, a study by Murthy et al, showed no OBC in patients who underwent PM; however, they found ADH in 1.7% of cases, followed by ductal carcinoma in situ (DCIS) in 1%, lobular carcinoma in situ in 1.3%, whereas they did not identify positive nodes on SLNB in PM cases. ¹¹ We found that 11.5% of patients had ADH on PM, along with persistent negative SLNB results on routine PM/CPM. Another study reported an overall rate of occult malignancy as 0.8% and identified DCIS in 3.5% of their cases; they correlated OBC identification to increasing patient age, prior history of BC, and higher BI-RADS score, that is, ⩾III on preoperative imaging, therefore, suggested to skip SLNB safely in PM cases where appropriate.^4,5 Another study identified the OBC rate as 11.3% with the majority having DCIS. ²¹ Similarly, over the years, it is found safe to skip SLNB when in situ disease is identified on mastectomy. ⁶ Therefore, our data are consistent with larger studies globally which have statistically demonstrated that it can be safely skipped, but the total number of nodal data in this context is only 8, which lacks statistical significance. Thus, our data are suggestive and consistent with data from larger studies where they established the fact that SLNB can be safely skipped seeing low OBC and in situ disease presence among patients unless other high-risk factors warrant otherwise. In our cohort, the identification of ADH was also linked to metaplastic carcinoma in 66.6% of cases, which is like the Kurian and Al-Nafussi ²² cohort, where they reported ADH/DCIS identification in ⩾50% of metaplastic carcinomas; however, they did not study genetic association in their cohort. Studies have reported that the subsequent increase in the BI-RADS scores increases the likelihood of BC diagnosis, which is also reflected in our results where 33.3% of patients with ADH diagnosis had BI-RADS IV on preoperative imaging.^{21 -24} Hence, the decision to undertake SLNB in CPM cases should rely on cumulative high-risk factors, including the patient’s age, BC subtype/grade, and preoperative BI-RADS score. ⁵

In comparison with conventional radiography, MRI has a sensitivity and accuracy of 94% and 80%, respectively, and can identify high-risk mutant carriers at an earlier stage.^25,26 Its higher cost, which is evident in our study’s limited uptake – likely due to financial limitations in LMICs – comes with a drawback, in that it is less widely used. The BGICC (Breast Gynecological & Immunooncology International Cancer Conference) consensus, which was conducted in 2020 for LMIC, concurred that women with an estimated BC risk of 20% to 25% should have MRI included in imaging regardless, but they also suggested future trials and research, to propose an alternative to resource-poor nations. ²⁵

To the best of our knowledge, it is a pioneer study from Pakistan that looks for the OBC identification among our patients undergoing PM/CPM due to high-risk HRBC genes, along with the correlation of histopathologic and radiological parameters in PM/CPM cases and its implications on SLNB uptake. However, our study has limitations of the small sample size, the retrospective type, and the sample belonging to a single tertiary-care unit; therefore, we cannot generalise the results for other units/hospital setups in the country. Also, the questionnaire used was not pretested before; therefore, it is one of our limitations.

However, the results will show future directions to the researchers to identify the prevalence of OBC and genetic mutations in our population using a large cohort to identify the patient populations where the benefit of SLNB is negligible in PM. It is high time now to formulate the guidelines that fit our patient population, rather than following the guidelines proposed by the West, where the population characteristics differ from ours. Our results also reinforce the concept of multidisciplinary decision-making among mutation carriers to correlate radiological, pathological, and overall high-risk factors in clinical decision-making regarding SLNB uptake. By downstaging the expected course of surgery for PM/CPM, both cost-effectiveness and procedure-related distress can be addressed among patients, and it will also have implications on the health care of LMICs as the available resources can be directed to the eligible patient population.

Conclusions

Our study shows negative OBC identification in PM cases with persistently negative SLNB results. However, we identified ADH in 11.5% of PM specimens. Our results suggest that SLNB can be safely omitted in patients undergoing PM/CPM as is shown in literature as well. However, factors like the BC status along with histopathological and radiological parameters are a cornerstone in decision-making for these patients. Furthermore, larger-scale studies are required in LMIC to get statistically significant results.