Clinical presentations and outcomes of young women aged <40 yrs with Ductal carcinoma in situ

Abstract

INTRODUCTION:

Ductal carcinoma in situ (DCIS) in young women is rare and not well studied. Since they do not qualify for mammographic screening, they are more likely to present with symptoms. Young women have also been associated with poorer outcomes, but it is unknown whether presentation mode affects outcome. We aimed to compare characteristics of DCIS patients <40 years of age presenting with symptoms versus those without, and determine whether presentation mode affects recurrence.

METHODS:

Pure DCIS patients aged <40 years were retrospectively analyzed. Clinical presentation, pathology and recurrence data were collected. Statistical analysis was performed to investigate the correlation of presentation mode with outcomes.

RESULTS:

40 patients with 41 cases were included. The mean age at diagnosis was 32.3 years (range 17–39). 73.2% and 26.8% presented with symptoms or abnormal imaging respectively. Of the cases who presented with symptoms, 86.7%, 10.0% and 3.3% had palpable lump, nipple discharge or breast pain, respectively. The average tumor size was 22.0 mm (range 2.0–86.9) and 12.2 mm (range 3–25) for patients who presented with symptoms and non-symptomatic group, respectively. Cases presenting with symptoms were statistically associated with higher grade (p = 0.0090). On median follow-up of 85 months, there were 3 (7.3%) recurrences, which were not statistically associated with presentation mode.

CONCLUSION:

Young women with DCIS tend to present with symptoms, with breast lump as the commonest symptom. Symptomatic patients tend to be associated with grade III tumours, compared to non-symptomatic patients. On long-term follow-up, mode of presentation was not statistically associated with recurrence.

Keywords

Breast cancer DCIS

1. Introduction

Ductal Carcinoma in situ (DCIS) is a pre-invasive disease and is typically asymptomatic [1]. DCIS manifests most commonly as microcalcifications on mammogram [2] and accounts for about 20% of all newly diagnosed breast cancers through screening [3]. However, little is known of DCIS in young women, as it is an uncommon disease in younger women, accounting for less than 4% of all breast cancers [4].

Young women with DCIS have certain characteristics. First, because young women do not qualify for mammography screening, they tend to be diagnosed with cancer by presenting with symptoms instead—such as a palpable breast lump, breast pain or nipple discharge, etc. Second, while DCIS has been associated with an excellent prognosis, younger women with DCIS, on the other hand, have been known to have more aggressive disease with a higher locoregional recurrence rate [5–8].

Since screen-detected asymptomatic DCIS tends to have a better prognosis compared to symptomatic DCIS [9], it is not known if DCIS in young women would also behave in a similar manner. We aimed to compare the characteristics of young women with DCIS presenting with symptoms versus those without symptoms and determine whether mode of presentation affects outcome.

2. Patients and methods

Young women <40years treated for DCIS, at a tertiary centre from 1st September 2005 to 31 October 2017, were identified from a prospectively maintained database. Patients with microinvasive or invasive cancer or those who declined treatment were excluded. Clinical presentation, radiological and pathological findings, and recurrence data were collected.

Breast conserving surgery or mastectomy, with or without reconstruction, would be performed based on factors such as the patient’s tumour to breast size ratio, number of foci of tumour, patient preference, etc. For this study, margins were considered clear in breast conserving surgery if they were ≥2 mm from the DCIS [10].

The management of the patients was discussed at a multidisciplinary tumor board for their individualised treatment. Generally, patients who underwent breast conservation surgery would be advised to receive adjuvant radiation, unless the DCIS was small. In patients with hormone positive DCIS, the option of adjuvant hormonal therapy would be discussed. In view of their young age at disease diagnosis, patients would routinely be referred to genetic clinics.

Subsequent to adjuvant therapy, patients were followed up at 3–4 monthly intervals for the first 2 years, followed by 6-month intervals in the 3rd to 5th year, and then yearly thereafter. Annual surveillance imaging with bilateral mammography was performed for patients who had breast conserving surgery. In patients who had mastectomy, mammogram would be performed only on the contralateral breast.

In this study, recurrence was defined as a second cancer in the ipsilateral breast and/or ipsilateral lymph nodes, or distant metastasis of breast origin. Length of follow up was calculated from the date of surgery to either the last known follow-up date or date of recurrence.

3. Statistical analysis

Fisher’s exact test was used to compare categorical characteristics and outcomes between patients presenting with symptoms versus those without symptoms, with p < 0.05 defined as statistically significant. SAS statistical software (v9.4) was used for the analysis.

The study was approved by SingHealth Centralised Institutional Review Board (CIRB Ref: 2020/2147). Patients’ informed consents were waived by the ethics committee.

4. Results

During the study period, a total of 443 patients was treated for DCIS. Of these patients, 41 cases in 40 (9.0%) patients were aged younger than 40years. 1 patient had metachronous bilateral DCIS. The mean age at diagnosis was 32.3 years old (range 17–39). 30 cases (73.2%) presented with symptoms. Of these cases, 86.7%, 10.0% and 3.3% presented with a palpable lump, nipple discharge and breast pain respectively (Table 1). The average tumor size was 22.0 mm (range, 2.0–86.9) and 12.2 mm (range, 3–25) for the group of cases presenting with and without symptoms, respectively.

There were 26 patients who (63.4%) underwent breast conserving surgery with 34.6% of these patients also receiving adjuvant radiotherapy. Of the 38 patients with known ER status, 33 patients (86.8%) had ER positive disease. Of these 33 patients, 15.2% received hormonal therapy. 18 (43.9%), 11 (26.8%), 12 (29.3%) patients had grade I, II, III DCIS, respectively.

The uptake from patients for genetic clinic was low at 12.8%. Of the 5 patients who agreed to a genetic clinic review, 4 underwent genetic testing; 2 patients had no genetic mutations whilst 2 patients had variants of unknown significance.

On median follow-up of 85 months, there were 3 (7.3%) recurrences (1 distant and 2 local), all of which occurred in the group of patients presenting with symptoms. 2 of these patients had breast conserving surgery, and 1 patient also received adjuvant radiotherapy.

On statistical analysis, patients who presented with symptoms were statistically associated with a higher grade (p = 0.0090). However, recurrence was not statistically associated with the mode of presentation.

Table 1
Characteristics of patients aged <40years old with ductal carcinoma in situ (DCIS)

Presented with symptom N = 30 (%) Presented with no symptoms N = 11 (%) P value^∗

Age (years) 0.3969

<20 3 (10.0) 0 (0)

20–29 7 (23.3) 1 (9.1)

30–39 20 (66.7) 10 (90.9)

Clinical presentation NA

Breast lump 26 (86.7) NA

Nipple discharge 3 (10.0) NA

Breast pain 1 (3.3) NA

Radiological findings 0.4462

Benign 5 (18.5) 0 (0)

Indeterminate 16 (59.3) 8 (72.7)

Suspicious 6 (22.2) 3 (27.3)

Not done 3 0

Pathological features

Tumor size (mm) 0.7234

≤20 19 (67.9) 8 (72.7)

>20–50 6 (21.4) 3 (27.3)

>50 3 (10.7) 0 (0)

Unknown 2 0

Grade 0.0090

I 13 (43.3) 5 (45.5)

II 5 (16.7) 6 (54.5)

III 12 (40.0) 0 (0)

Estrogen receptor (ER) 0.2984

Positive 23 (82.1) 10 (100.0)

Negative 5 (17.9) 0 (0)

Unknown 2 1

Progesterone receptor (PR) 0.6464

Positive 18 (75.0) 7 (87.5)

Negative 6 (25.0) 1 (12.5)

Unknown 6 3

Surgery 0.7158

Mastectomy 12 (40.0) 3 (27.3)

Breast conserving surgery (BCS) 18 (60.0) 8 (72.7)

Hormonal therapy (for 33 ER positive cases only) 0.1493

Yes 2 (8.7) 3 (30.0)

No 21 (91.3) 7 (70.0)

Radiotherapy (after BCS in 26 cases) 0.3821

Yes 5 (27.8) 4 (50.0)

No 13 (72.2) 4 (50.0)

Recurrence 0.5511

Yes 3 (10.0) 0 (0)

No 27 (90.0) 11 (100)

	Presented with symptom N = 30 (%)	Presented with no symptoms N = 11 (%)	P value^∗
Age (years)			0.3969
<20	3 (10.0)	0 (0)
20–29	7 (23.3)	1 (9.1)
30–39	20 (66.7)	10 (90.9)
Clinical presentation			NA
Breast lump	26 (86.7)	NA
Nipple discharge	3 (10.0)	NA
Breast pain	1 (3.3)	NA
Radiological findings			0.4462
Benign	5 (18.5)	0 (0)
Indeterminate	16 (59.3)	8 (72.7)
Suspicious	6 (22.2)	3 (27.3)
Not done	3	0
Pathological features
Tumor size (mm)			0.7234
≤20	19 (67.9)	8 (72.7)
>20–50	6 (21.4)	3 (27.3)
>50	3 (10.7)	0 (0)
Unknown	2	0
Grade			0.0090
I	13 (43.3)	5 (45.5)
II	5 (16.7)	6 (54.5)
III	12 (40.0)	0 (0)
Estrogen receptor (ER)			0.2984
Positive	23 (82.1)	10 (100.0)
Negative	5 (17.9)	0 (0)
Unknown	2	1
Progesterone receptor (PR)			0.6464
Positive	18 (75.0)	7 (87.5)
Negative	6 (25.0)	1 (12.5)
Unknown	6	3
Surgery			0.7158
Mastectomy	12 (40.0)	3 (27.3)
Breast conserving surgery (BCS)	18 (60.0)	8 (72.7)
Hormonal therapy (for 33 ER positive cases only)			0.1493
Yes	2 (8.7)	3 (30.0)
No	21 (91.3)	7 (70.0)
Radiotherapy (after BCS in 26 cases)			0.3821
Yes	5 (27.8)	4 (50.0)
No	13 (72.2)	4 (50.0)
Recurrence			0.5511
Yes	3 (10.0)	0 (0)
No	27 (90.0)	11 (100)

NA- not applicable. ^∗Fisher’s exact test.

5. Discussion

Young women <40years old with DCIS accounted for 9.0% of all patients with DCIS in our cohort. Majority of patients were symptomatic with 73.2% of patients presenting with symptoms. Breast lump was the most common reason for presentation. Majority (63.4%) of patients underwent breast conserving surgery, with 34.6% of these patients also receiving adjuvant radiotherapy. ER positive disease was present in 86.8% of patients of which 15.2% received hormonal therapy. Patients presenting with symptoms had higher grade (p = 0.0090). Recurrence was not statistically significant between cases presenting with symptoms versus those who did not. To the best of our knowledge, this is the first study comparing outcomes in young women with DCIS presenting with symptoms versus those who did not.

DCIS is diagnosed almost solely by mammogram, and its incidence has been increasing due to widespread use of mammogram screening. Locally, DCIS accounted for 26% of all screen-detected breast cancers [11]. Mammogram screening is recommended every 2 years for ages ≥50 years. At 40–49 years of age, mammogram screening could be offered annually, after a discussion of its risks and benefits. For younger women of average risk aged <40 years, only monthly breast self-examination is advocated. This local screening guideline was formulated because DCIS constituted >30% of all breast cancers among pre-menopausal women, which largely constituted women aged 40 to 49 years [11].

DCIS is uncommon in young women, and because they do not qualify for mammogram screening, most of these young women with DCIS presented with symptoms. In our study, these patients who presented with symptoms tended to exhibit higher grade compared to those who did not present with symptoms. Although the literature indicates high grade as a risk factor for recurrence [12,13], our study showed that the mode of presentation was not a statistically significant risk factor for recurrence, even though all recurrences occurred in the symptomatic group. This may be due to the small numbers in our study and there may be other implicating risk factors for recurrence.

Patients <40 years old diagnosed with DCIS have generally been shown to have a poorer prognosis with a tendency towards higher recurrence [14--16], although some studies have shown that young age alone is not a significant predictor of poor prognosis [12]. As a result, there was a trend in some countries for younger women with DCIS to opt for mastectomy as well as contralateral risk reducing mastectomy [17,18]. A recent study, however, cautioned against excessively aggressive treatment, as mastectomy did not offer better survival benefits over breast conserving surgery with radiotherapy [14]. In our study, although the majority of cases underwent breast conservation surgery, our recurrence rate was comparable with the literature, which reported a 5-year local recurrence rate of 10.1% in women aged <40 years [13].

While radiotherapy following breast conserving surgery confers a risk reduction of ipsilateral tumour recurrence, this risk reduction of adjuvant radiotherapy appeared to be smaller in younger women aged <40 years old [19]. The role of adjuvant radiotherapy in young patients with DCIS needs to be clarified with further studies.

Adjuvant endocrine therapy in hormone positive DCIS has been purported to decrease invasive recurrence, although it has not been established to improve survival [20]. A recent large study reported an uptake of endocrine therapy in young women with DCIS aged ≤30 at 18.1% [20], which was comparable with our study. Patient refusal was one of the reasons cited for the low uptake of endocrine therapy. This was likely due to perceived side effects of endocrine therapy and its effects on fertility.

There is currently no consensus whether younger patients with DCIS should be treated more aggressively. This is because not only are they relatively rare, there were different age cut-offs used in various studies to define young patients with DCIS, with some studies using <35, <40 and even <50 years old as a cut-off age. In this study, <40 years old was chosen as the cut-off age because mammography screening is offered locally to patients aged ≥40 years. Nevertheless, with the evolving landscape of the DCIS treatment, it is important to optimize DCIS adjuvant treatment in this young subgroup of patients.

Strengths of the study include that patient’s data, including recurrence data, were well-kept in a prospectively maintained database. This is the first study in young women with DCIS to determine if their presentation mode would specifically affect their outcomes, providing further insights into the management of this rare entity.

The study is not without limitations. As a retrospective study, it was not possible to correlate in all cases whether the presenting symptom coincided with the site of DCIS or was related to DCIS. However, we were able to distinguish reliably from the clinical records if the patient had breast symptoms upon first consult. Interestingly, while patients in this group could present with breast pain [21], breast pain is generally not associated with breast cancer [22]. Another limitation was that there may be selection bias in the treatment regime. However, the treatment of these cases was individualised and discussed in the multidisciplinary meeting. There was also no statistical difference in the treatment regimens between the cases who presented with symptoms versus those who did not.

In conclusion, DCIS in young women is uncommon. They tend to present with symptoms and have a great likelihood of grade III tumour, compared to asymptomatic patients. Mode of presentation did not affect recurrence though this finding was based on a small sample size. Larger studies should be done to validate our findings. Treatment should be individualised based on patient’s tumor characteristics.

Footnotes

Ethical approval

The study was approved by SingHealth Centralised Institutional Review Board (CIRB Ref: 2020/2147). Patients’ informed consents were waived by the ethics committee.

Conflicts of interest

The authors declare no conflicts of interest.

Availability of Data and materials

The data are available from the corresponding author upon request.

Funding

There was no funding for this study.

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