Advanced hormone receptor-positive/human epidermal growth factor receptor 2-positive invasive ductal carcinoma with cecal metastasis: A case report

Abstract

The incidence of gastrointestinal metastases from breast cancer (BC) is low. We report a special case of Luminal B (Hormone Receptor positive [HR+]/Human Epidermal Growth Factor receptor 2-positive [HER-2+]) BC. The patient presented with asymptomatic brain metastases two years after radical surgery for modified breast cancer and developed right lower abdominal pain during relief therapy. Electronic gastroenteroscopy revealed inflammatory changes in the cecal mucosa. These changes were confirmed on pathology to be cecal metastasis from BC. The patient's condition was stabilised after treatment with an antibody-drug conjugate (ADC). For patients with BC who develop appendicitis-like symptoms after treatment for invasive ductal carcinoma of the breast, clinicians should be fully aware that the possibility of cecal metastasis needs to be considered, despite the very low probability of occurrence.

Introduction

Breast cancer (BC) is the most common cause of death from cancer in women. Mortality from BC has decreased as therapies are improving.^1–4 The proportion of human epidermal growth factor receptor 2-positive (HER-2+) BC is high (20% to 25%), and about half of these cases are also hormone receptor–positive (HR+). HR+/HER-2+ BC is highly aggressive, with frequent recurrence and a poor prognosis. The common metastatic sites of BC include the lungs, liver, bone, and brain, ⁵ but some patients may develop intestinal tract metastases, such as cecal metastasis. Because the clinical manifestations are often nonspecific, such metastases are often missed or misdiagnosed as primary intestinal tumors. Among BC metastases to the intestinal tract, due to the special anatomical location, cecal metastases are very rare. This has contributed to the lack of treatment guidelines for BC with cecal metastasis.

However, due to the special anatomical location of the cecum and the nonspecific symptoms of cecal metastasis, early diagnosis of cecal metastasis from BC is difficult. We aimed to describe a case of cecal metastasis in an individual with HR+/HER-2+ invasive ductal carcinoma (IDC). The relevant literature is also reviewed.

Case presentation

A 53-year-old Chinese woman who complained of intermittent pain in the lower right abdomen with nausea and vomiting was admitted to the hospital in September 2021.

She complained of intermittent pain in the lower right abdomen with nausea and vomiting beginning one month prior like appendicitis but had no trouble swallowing, constipation, or diarrhea. The patient had no palpable mass and no other clinical symptoms, such as tenderness, rebound tenderness, or mobile turbid sounds. Cancer antigen 125 (CA125), CA153, and CA199 were within normal limits.

There was no family history of cancer. However, in 2018, the patient had been admitted to a tertiary hospital in China due to a painless mass in the right breast and underwent a needle biopsy of the right breast mass. Pathologic examination confirmed the lesions were IDC. Results of immunohistochemistry indicated that the tumor was positive for estrogen receptor (ER) (+, 60%), progesterone receptor (PR) (+, 40%), Ki-67 (+, 10%), and c-erbB2 (2+). The patient then underwent a right axillary lymph node biopsy, which confirmed the presence of an ER (+, 90%), PR (+, 40%), Ki-67 (+, 30%), and c-erbB2 (3+) tumor. The patient received eight cycles of neoadjuvant chemotherapy, including cyclophosphamide, epirubicin, and docetaxel combined with trastuzumab. Several months later, the patient underwent a modified radical mastectomy. Postoperative pathology showed residual IDC and involvement of the left axillary lymph nodes (3/11). Immunohistochemistry demonstrated ER (+, 80%), PR (+, 30%), Ki-67 (+, 30%), and c-erbB2 (2+). Local radiotherapy was administered, and trastuzumab therapy was continued for one year after radiotherapy was completed. Patients underwent endocrine therapy of letrozole for almost two years. Afterward, magnetic resonance imaging revealed metastasis to the left cerebellar hemisphere in April 2021, although the patient was asymptomatic. The patient underwent stereotactic radiotherapy to the brain and was also treated with pyrotinib and fulvestrant.

The patient's gastroenteroscopy showed inflammatory changes in the cecal mucosa at this time. However, a biopsy of gastroenteroscopy results indicated cecal carcinoma. For most markers, we could not count the number of positive cells due to the small amount of tissue collected. Immunohistochemistry only showed that the tumor cells were positive for ER (Figure 1(a)), GATA-binding protein 3 (GATA3) (Figure 1(b)), CK7, Ki-67 (Figure 1(c)), and HER-2 (Figure 1(d)). Expression of CK20, a marker for gastrointestinal metastasis of BC and PR (Figure 1(e)), was negative. The statuses of all markers of primary BC, lymph node metastasis, and cecal metastasis are presented in Table 1.

Figure 1.

Immunohistochemical images from patients with cecal metastases. Shows expression of representative immunohistochemical markers.

Table 1.

Immunohistochemical staining results of the primary breast cancer, lymph node metastasis, and cecal metastasis.

		ER	PR	Ki-67	HER-2	GATA3	CK7	CK20
Primary breast cancer	Biopsy	+, 60%	+, 40%	+, 10%	2+
	Surgery	+, 80%	+, 30%	+, 30%	2+
Lymph node metastasis	Biopsy	+, 90%	+, 40%	+, 30%	3+
Cecal metastasis		+	−	+, 2%	+	+	+	−

ER: estrogen receptor; PR: progesterone receptor; HER-2: human epidermal growth factor receptor 2-positive; GATA3: GATA binding protein 3; CK7: cytokeratin 7; CK20: cytokeratin 20.

Because of the rarity of the case, a tumor board was assembled to discuss further treatment. The patient completed six times of ADC (Disitamab Vedotin). After treatment with ADC, no new metastasis was observed. Also, the side effects of Disitamab Vedotin were tolerable. The follow-up is ongoing. At the time of writing this article, the patient's disease is stable.

Discussion

BC is the main cause of cancer-related death in women. ⁴ The most common metastatic sites are the lungs, liver, bone, and brain, whereas the gastrointestinal tract is a rare metastatic site,^5–7 with a metastatic rate of less than 5% among all BC patients. ⁷ The most common locations of gastrointestinal tract metastases from BC are the large intestine (cecum, colon, and rectum), followed by the small intestine (duodenum and ileum), and finally the anus. Analysis of BC metastatic sites in 1238 patients showed a significant correlation between the pathological type of BC and the metastatic sites. For example, invasive lobular carcinoma (ILC) most often metastasizes to the bone marrow and peritoneum, whereas IDC most often metastasizes to the lungs, pleura, and bone. ⁸ Interestingly, BC metastases to the extrahepatic gastrointestinal tract usually originate from the lobular carcinoma subtype. In one study, ILC was diagnosed in 12% of primary BC cases, yet it accounted for 64% of gastrointestinal metastases. ⁹ To our knowledge, the present case is one of the few reports of HER-2+ IDC metastasis to the cecum.

Early diagnosis of gastrointestinal metastases from BC is very challenging. Most BC patients with gastrointestinal metastases, even those with multiple locations, usually have nonspecific symptoms. Patients may experience abdominal pain, nausea, vomiting, unexpected weight loss, and fatigue. Intestinal obstruction and bleeding can also occur. The variable symptoms of gastrointestinal metastasis and the variable time interval between primary diagnosis and metastasis pose major clinical challenges to the diagnosis of gastrointestinal metastases from BC.

Endoscopic, radiologic, and histologic evaluations are useful in distinguishing primary from metastatic gastrointestinal cancer. In the early stage of metastasis, endoscopy may reveal either normal or slightly inflamed mucosa, thereby limiting the usefulness of the technique. Due to the lack of specificity of symptoms of gastrointestinal metastasis, different patients experience different symptoms and also require different treatment measures (Table 2). In one instance, metastatic BC presented with symptoms similar to colitis, and a biopsy showed necrotic tissue without any malignancy. Histopathology after the patient underwent radical surgery confirmed the colonic metastasis of breast lobular carcinoma. ¹⁰ Another report detailed the experience of a 72-year-old woman treated for BC who presented three years later with abdominal pain, intermittent vomiting, persistent constipation, and intestinal obstruction. The patient underwent an emergency right hemicolectomy. Subsequently, cecal metastatic disease was found.^11,12

Table 2.

Reported cases of gastrointestinal metastasis from breast carcinoma.

Author	Year	Number of patients	Age (yr)	Months from diagnosis	Histology	Symptoms	Treatment	Ref.
Okido et al. 10	2011	1	48	60	ILC	A mobile abdominal mass	Resection of the transverse colon, a lymph-adenectomy, primary anastomosis and targeted therapy (trastuzumab)	10
Birla et al. 11	2008	1	72	36	ILC	Abdominal pain, intermittent vomiting	Hemicolectomy	11
Rajan et al. 12	2012	1						12
			60	108	IDC	Rectal bleeding	Pre-operative radiotherapy, a low anterior resection with end colostomy formation.

DC: Ductal carcinoma; ILC: Invasive lobular carcinoma.

In our case study, we only observed inflammatory changes in the cecum during electronic gastroenteroscopy, and we confirmed cecal metastasis by pathological examination. For some patients, endoscopic findings of metastatic cancer can include ulcers, thickened or fragile mucous membranes, flaky inflammation, stenosis, polyps, and obstructive masses. ¹³ Therefore, our findings suggest that electronic gastroenteroscopy has important value in diagnosis. For some early suspected inflammatory lesions, an electronic gastroenteroscopy should be performed as soon as possible after the discovery of cancer lesions through localized biopsy. Hence, for patients who are exhibiting gastrointestinal symptoms and have a history of cancer, clinicians should consider the possibility of tumor metastasis.

However, electronic gastroenteroscopy is not the first choice for patients with symptoms of gastrointestinal obstruction; severe, unbearable pain; or serious conditions such as hemesis and hematochezia. For these cases, surgery should be performed promptly so that the etiology can be determined while the disease is treated and/or the symptoms are relieved.

Gastrointestinal metastases of BC are difficult to distinguish from primary gastrointestinal tumors. Immunohistochemistry is key to achieving an accurate diagnosis. BC-related biomarkers commonly used include ER, PR, CK7, CK20, villin, and GATA3. Villin is a protein expressed in the epithelial cells of the normal intestine. Negative villin expression indicates intestinal metastasis from other sources. GATA3 is a marker of primary or metastatic BC, and its expression is higher than mammaglobin, ER, and PR.^14,15 Metastatic BC is usually positive for CK7, CEA, ER, and PR, but positivity for CK7 and CEA is nonspecific.^16,17 Because CK20 is almost always present in gastrointestinal tumors but not in BC, a CK7−/CK20 + expression pattern is consistent with primary colorectal tumors. ¹⁸ Some variations have been reported, such as villin-ER−/CEA-CK20 + tumors. ¹⁹ In our case study, the patient's tumor was found to be ER+, GATA3+, and CK7+, and CK20−. HER-2 positivity was consistent with the primary lesion. Interestingly, the metastatic lesion was PR−. This may also be related to the heterogeneity of the receptor status within the tumor mass.

Metastatic BC with intestinal involvement may require surgery alone or in combination with systemic hormone therapy or chemotherapy. For patients with isolated gastrointestinal disease, radical resection followed by biological therapy or chemotherapy may improve outcomes. For example, in one study, right hemicolectomy combined with vinorelbine and letrozole treatment achieved 20-month survival in an individual with ILC and late-presenting (i.e. 12 years after onset of ILC) metastatic colonic lesions. ²⁰ The patient in our case study developed cecal metastasis two years after surgery. Thus, the patient's disease-free survival was two years.

The incidence of HER-2+ BC with brain metastasis is high. Approximately 50% of individuals with BC will eventually develop metastases.^21,22 In our case study, following the occurrence of asymptomatic brain metastasis, the patient was treated with local radiotherapy combined with a newer therapy, intensive anti-HER-2 targeted therapy. However, disease progression occurred within five months. Because resistance to target therapy may progress, a more effective anti-HER-2 targeted therapy, ADC (Disitamab Vedotin), was selected to treat the patient. Disitamab Vedotin is formed by coupling trastuzumab to Microtubule inhibitor Orratatin E through a thioether linker. Disitamab Vedotin retains the effect of trastuzumab and targets HER2, and it then releases the cytotoxic antimicrotubular agent. Like T-DM1, a dual agent is more effective than trastuzumab alone. ²³

Conclusion

Although uncommon, the possibility of gastrointestinal metastases from BC should be investigated in individuals with intestinal symptoms and a history of primary BC tumor. In making a diagnosis, appropriate imaging, endoscopy (including systematic screening, deep biopsy, or resection), and immunohistochemistry of biopsy samples are necessary. Immunohistochemistry is especially useful in defining the tumor tissue of origin. For individuals with HER2+ tumor expression, anti-HER2 therapy should be considered. Due to the rarity of these situations and the lack of systematic research, the treatment plan and long-term prognosis of patients remain unclear. Multicenter research or clinical trials are necessary in the future.