Pathological Complete Response with Neoadjuvant Trastuzumab, Pertuzumab, and Chemotherapy Followed by Modified Radical Mastectomy in a Patient with HER2-Positive Occult Breast Cancer

Introduction

Breast cancer is the most common cancer globally, with an estimated 2 308 897 new cases in 2022 and 665 684 related deaths [1]. Over the past few years, the incidence of breast cancer among Chinese women, especially those living in cities, has substantially grown each year [2]. Human epidermal growth factor receptor 2 (HER2) positivity is a key prognostic factor [3]. Before 2005, it was a predictor of poor prognosis because HER2-positive cancers are aggressive, but the advent of targeted therapies against HER2 improved the prognosis [4]. Early diagnosis and treatment are the key to improving breast cancer prognosis [5]. Several countries now have breast cancer screening programs that effectively reduce breast cancer morbidity and mortality [6]. Still, breast cancer screening programs are far from perfect, with risks of false-positive and false-negative results [7,8].

Occult breast cancer is rare and is of particular concern because it is usually diagnosed when regional or distant metastases are found without evidence of a primary tumor [9]. For instance, cancer was found in about 20% of those with persistently enlarged lymph nodes, and 50% of such cancers are of breast origin [10–12], while most enlarged lymph nodes are of infectious origin [13]. When the diagnosis of occult breast cancer is confirmed, the choice of optimal treatment strategy is challenging [14–16]. The National Comprehensive Cancer Network (NCCN) guidelines state that axillary lymphatic lesions should be tested for breast cancer markers; if the lesions are revealed as of mammary origin, the patient should be treated according to the breast cancer guidelines according to the molecular characteristics of the lesion [15,16]. Neoadjuvant chemotherapy before breast and axilla surgery may be an effective strategy in the absence of a detectable primary tumor [14]. Patients with HER2-positive breast cancer should receive HER2-targeted treatments, such as trastuzumab and pertuzumab [15]. HER2 testing can be done using immunohistochemistry and fluorescence in-situ hybridization (FISH) [17]. Cases of occult breast cancer are rare.

In reported cases, OBC patients typically present with invasive and undetectable primary breast tumors, with metastatic lesions that can be found in the axillary lymph nodes, ovaries and thyroid glands. In addition to biopsy, mammography, ultrasound, and magnetic resonance imaging (MRI), and even positron emission tomography (PET) and laparoscopy can be used to diagnose patients. Previous reports suggest that the treatment of OBC patients should be individualized and include, but are not limited to, targeted agents, chemotherapeutic agents, radiotherapy, or surgery, either alone or in combination [18–22].

This report aims to present the case of a woman diagnosed with HER2-positive occult breast cancer who achieved pathological complete response after the TCbHP (trastuzumab, pertuzumab combined with docetaxel and carboplatin) neoadjuvant chemotherapy regimen, which may provide a valuable reference for clinicians in treating similar cases.

Case Report

A 43-year-old woman was admitted to the hospital 6 months after detecting a lump in her left axilla, about the size of a quail egg, but not red or swollen. It was slightly painful but caused no nipple discharge. It was not taken seriously, and no treatments were given. The lump gradually grew, and the patient underwent a color Doppler ultrasound at a local hospital on February 12, 2022, revealing several hypoechoic lesions in the left axilla, with the largest one being 54×31×24 mm, suggesting the possibility of abnormal lymph nodes. The patient was admitted to the First Affiliated Hospital of Bengbu Medical College for further diagnosis and treatment.

Physical examination showed no palpable masses in the breasts or orange-peel sign. There were several enlarged lymph nodes in the left axilla (the largest being about 5.0 cm in diameter; some were fused) with a firm texture and average mobility, without skin redness or swelling. A mammography on February 15, 2022, showed no obvious abnormal nodules in bilateral breast glands. The left axilla mass was visible on mammography (Figure 1). According to the color Doppler ultrasound (Figure 2), no lesions were detected in either breast, but several hypoechoic echoes (the largest being 32×42 mm) were detected on the edge of the outer glandular layer of the left breast and under the left axilla. The echoes were irregular in form and poorly defined in contour, with abundant blood flow signals. Enhanced magnetic resonance imaging (MRI) revealed that both mammary glands were symmetrical, with a small number of fibrous glands, and both mammary glands had smooth surfaces. The skin and areolae were not thickened, and the subcutaneous fat layers were clear. Multiple enlarged lymph nodes presenting abnormal T1 and T2 signals (the largest being approximately 51×39 mm), with coarse edges and surrounding exudation, were detected in the left axilla, some which some invaded the left pectoralis major. Moreover, the diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) presented a high and slightly low signal, respectively, and the ADC was approximately 1.055–1.211×10−3 mm2/s. The lesions showed heterogeneous enhancement, and the time-signal intensity curve (TIC) was of the outflow type. Maximum intensity projection (MIP) showed that the tissues around the lesions were thickened and had dilated vascular shadows (Figure 3). A core-needle biopsy of the largest left axillary lymph node was performed on February 18, 2022, revealing a metastatic invasive carcinoma (Figure 4). The histological subtype could not be conclusively determined from the biopsy. The lesion was an invasive carcinoma, non-specific type, grade III, consistent with a breast origin. Immunohistochemistry showed that the tumor cells were estrogen receptors (ER)-negative, progesterone receptor (PR)-negative, HER2-positive (3+) (by immunohistochemistry only, FISH was not necessary), Antigen Kiel 67 (Ki-67)-positive (+, approximately 60%), gross cystic disease fluid protein 15 (GCDFP-15)-positive (3+), mammaglobin (1+), and p53 (3+) (Figure 5). Therefore, the patient was finally diagnosed with occult breast cancer of the left breast, cT0N2M0, stage IIIA. The molecular typing was hormone receptor (HR)-negative, HER2-positive.

The TCbHP (trastuzumab, pertuzumab combined with docetaxel and carboplatin) neoadjuvant chemotherapy regimen was given according to the 2021 Chinese Society of Clinical Oncology (CSCO) breast cancer guidelines [23]. Docetaxel (75 mg/m2), carboplatin (area under the curve [AUC]=6), trastuzumab (initial dose of 8 mg/kg, subsequent doses of 6 mg/kg), and pertuzumab (initial dose of 840 mg, subsequent doses of 420 mg) were administered intravenously on day 1 of every 21-day cycle, for 6 cycles. The last treatment was performed on June 29, 2022. A modified radical mastectomy on the left breast was performed under general anesthesia on July 14, 2022. No tumor tissue was detected in the surgical specimen, suggesting a pathological complete response (pCR). Significant interstitial fibrosis, collagenization, and adenopathy were detected. The nipple and the skin were negative. All 20 lymph nodes were negative. Radiotherapy was conducted in September 2022. Trastuzumab and pertuzumab were continued.

Discussion

Here, we report a case of an occult, aggressive, HER2-positive breast cancer without breast lesion, detected by breast ultrasound, ultrasound, and MRI, indicating that aggressive breast cancers can spread regionally despite a primary lesion being too small or diffuse to be detected. The core-needle biopsy confirmed that the axillary lesion was malignant and was HER2-positive. After TCbHP neoadjuvant therapy and surgery, a pCR was observed, suggesting a good prognosis. Due to the low incidence and few cases of occult breast cancer, the treatment strategies for such cancer are not supported by a large volume of sample data. Therefore, the present paper presents the manifestation, diagnosis, and treatment plan to provide more ideas regarding managing HER2-positive occult breast cancer.

Occult breast cancer is characterized by low incidence and clinical rarity [24]. Occult breast cancer in Western countries accounts for 0.3–1% of all cases of breast malignancy [24]. At present, the etiology of occult breast cancer remains unclear [25]. The mainstream view is that the body’s specific immune defenses inhibit the growth of the primary lesion, which manifests itself as microscopic lesions, or that fibrous mastitis promotes thickening of the breast tissue and deep lesions, affecting the detection of small primary lesions or the failure of diffuse lesions to form masses [25]. As in the case reported here, previous cases displayed aggressive HER2-positive breast cancer and an occult primary tumor [18–22], supporting that aggressive tumors can metastasize despite a primary lesion being too small or diffuse to be detected [26]. The initial symptom of occult breast cancer tends to be an axillary lump, and neither clinical examination nor imaging can detect a primary lesion [9]. Only the pathological examination of the lymph node(s) will suggest metastatic cancer and a possible breast origin [15]. There is currently no definitive diagnosis basis [9]. The presence of paraneoplastic syndromes, such as discomfort in the distal extremities, muscle weakness, and dermatomyositis, can also be the initial manifestations of occult breast cancer [27]. Determining the treatment plan based on the pathological diagnosis, histological biopsy, and immunohistochemistry is crucial [15,16]. Fine-needle aspiration cytology (FNAC) is easy to perform, causes minimal trauma, poses a low risk, and has a quick recovery, but FNAC takes only a limited amount of material, and the pathological diagnosis can be difficult [28]. In contrast, core-needle biopsy takes a larger amount of tissue and is more reliable for diagnosis [29].

The prognosis of occult breast cancer is greatly affected by the late diagnosis due to its occult nature [9,15,16]. The median age at onset of occult breast cancer is 60 years, and the 5- and 10-year survival rates are 78.2–82.8% and 58.0–63.0%, respectively [30]. The surgical management of breast cancer is usually selected based on the characteristics of the primary tumor and axilla [15]. In occult breast cancer, the surgery selection is also crucial, but the selection must be made without the characteristics of the primary cancer [9]. The common types of breast surgery include axillary lymph node dissection with breast conservation, mastectomy and axillary lymph node dissection, whole-breast radiation therapy and axillary lymph node dissection, and axillary lymph node dissection [15]. Considering the small number of cases reported, no differences can be determined among the surgical strategies [9,14,30,31].

Regarding systemic therapy, neoadjuvant chemotherapy can decrease tumor activity, shrink positive lymph nodes, reduce surgical trauma and difficulty, eliminate micro-metastases, assess the efficacy of chemotherapeutic drugs, and prevent the formation of drug-resistant strains [14,31–33]. Neoadjuvant chemotherapy has a certain therapeutic value for N2-3 occult breast cancer or occult breast cancer with axillary lymph nodes >4 cm [14,31–33]. For HER2-positive breast cancer, neoadjuvant chemotherapy combined with HER2-targeted therapy against HER2 can substantially improve patient outcomes [34]. In the TRYPHAENA trial, a neoadjuvant anthracycline-based chemotherapy regimen, combined with trastuzumab and pertuzumab, improved the pCR rate to 66% [35]. It has been suggested that the treatment principle for occult breast cancer is basically the same as for invasive breast cancer, which means an appropriate treatment scheme should be developed based on the patient’s condition [15,16]. Concurrently, equal emphasis should be placed on local treatment techniques such as surgery and radiation therapy and systemic treatment such as chemotherapy, endocrine therapy, targeted therapy, and immunotherapy [15]. In other words, the “personalized, whole-process, comprehensive, and full-lifecycle management” philosophy must be upheld.

Conclusions

This case highlights that even aggressive HER2-positive breast cancer can manifest as an occult primary tumor. Neoadjuvant chemotherapy followed by modified radical mastectomy can be an effective strategy for such cases.