Clinicopathological Factors Determining the Pathological Response to Neoadjuvant Therapy in HER2 Positive Breast Cancer

Abdullah Evren YETİŞİR; Semra PAYDAŞ

doi:10.4274/nkmj.galenos.2021.32932

ABSTRACT

Conclusion:

In this series of 54 cases with HER2 positive breast cancer, the parameters determining pathological complete response after neoadjuvant treatment are high Ki-67 proliferation index, grade III tumor and hormone receptor negativity.

Results:

Grade III tumor, hormone receptor negativity, high Ki-67 score, and the presence of T3 or T4 tumor were found to be better associated with pathological complete response (p=0.036, p=0.033, p=0.021, p=0.048, respectively). High tumor grade, hormone receptor negativity and high Ki-67 score were found as independent risk factors determining pathological complete response (p=0.043, p=0.047, p=0.035, respectively).

Materials and Methods:

A total of 54 HER2 expression positive cases were included in this study. Neoadjuvant chemotherapy regimen containing trastuzumab was applied to all patients. Patients’ age, gender, disease stage, tumor size and lymph node status, estrogen and progesterone receptor status, Ki-67 proliferation index, tumor grade, menopausal status and pathological complete response status after neoadjuvant therapy, neoadjuvant treatment regimen and the relationship between the tumor and histological subtype were examined.

Aim:

In our study, we aimed to determine the clinicopathological factors affecting the pathological response after neoadjuvant chemotherapy in HER2 positive breast cancer.

Keywords:

Breast cancer, HER2, neoadjuvant, pathological complete response

INTRODUCTION

Breast cancer is the most common cancer seen in women. According to Globocan 2020, 23.9% of cancers seen in women in our country are breast cancer. Breast cancer is the second most common cause of cancer mortality in our country and in the USA^1,2. Neoadjuvant treatment of breast cancer refers to the systemic treatment of the tumor before surgery. In this way, by shrinking the tumor, breast-conserving surgery can be performed instead of mastectomy, and better cosmetic results can be obtained, and lymphedema that may develop after surgery can be prevented^3,4. Another important advantage of neoadjuvant therapy is that therapeutic efficacy can be directly observed⁵. It also provides the opportunity for personalized treatment strategies and drug development⁶. Human epidermal growth factor receptor 2 (HER2) is from the family of epidermal growth factor receptors that play a critical role in the activation of subcellular signal transduction pathways which control epithelial cell growth and differentiation^7,8. Amplification or overexpression of the HER2 oncogene is present in approximately 15% of invasive breast cancers⁹. Since the presence of HER2 expression is a predictive factor in breast cancer, HER2 expression status should be investigated at the time of diagnosis in breast cancer¹⁰. In this way, agents targeting HER2 receptors can be used in adjuvant or neoadjuvant therapy^11-13. To determine the response after neoadjuvant therapy, pathological evaluation of the primary tumor and axillary lymph node is performed, except for negative sentinel lymph node before treatment. The absence of breast and axillary tumors in surgical material indicates pathological complete response (pCR) and is associated with better survival^14,15. Even if HER2-targeting agents are not used in neoadjuvant therapy in HER2 positive breast cancers, they have better pathological response rates than HER2-negative patients^16,17. Obtaining pCR after the completion of neoadjuvant therapy and surgical resection is associated with improved disease-free survival. This correlation is dependent on the molecular subtype and is evident in patients with triple negative and HER2 positive breast cancer⁵.

In our study, we aimed to determine the factors affecting the pathological response after neoadjuvant chemotherapy in HER2 positive breast cancer.

GİRİŞ

Meme kanseri kadınlarda en sık görülen kanserdir. Globocan 2020’ye göre ülkemizde kadınlarda görülen kanserlerin %23,9’unu meme kanseri oluşturmaktadır. Kanser mortalitesinin 2. en sık sebebi ülkemizde ve ABD’de de meme kanseridir^1,2. Meme kanserinin neoadjuvan tedavisi cerrahi öncesi tümörün sistemik olarak tedavi edilmesini ifade eder. Bu sayede tümör küçültülerek mastektomi yerine meme koruyucu cerrahi yapılabilir ve kozmetik olarak daha iyi sonuç alınabilir, cerrahi sonrası gelişebilecek lenfödem engellenebilir^3,4. Neoadjuvan tedavinin diğer önemli bir avantajı terapötik etkinliğin doğrudan gözlemlenebilmesidir⁵. Kişiselleştirilmiş tedavi stratejileri ve ilaç geliştirme için de fırsat sağlar⁶. İnsan epidermal büyüme faktör reseptörü 2 (HER2) epitelyal hücre büyümesini ve farklılaşmasını kontrol eden subselüler sinyal iletim yollarının aktivasyonunda kritik rol alan epidermal büyüme faktörü reseptörü ailesindendir^7,8. HER2 onkogeninin amplifikasyonu veya aşırı ekspresyonu invaziv meme kanserlerinin yaklaşık %15’inde mevcuttur⁹. HER2 ekspresyonu varlığı meme kanserinde prediktif bir faktör olduğu için meme kanserinde tanı anında HER2 ekspresyon durumu araştırılmalıdır¹⁰. Bu sayede adjuvan veya neoadjuvan tedavide HER2 reseptörlerini hedefleyen ajanlar kullanılabilir^11-13. Neoadjuvan tedavi sonrası yanıtı belirlemek için, tedavi öncesi sentinel lenf nodu negatif olanlar hariç, primer tümörün ve aksiller lenf nodunun patolojik değerlendirmesi yapılır. Cerrahi materyalde meme ve aksillada tümörün olmaması patolojik tam yanıtı (pCR) gösterir ve daha iyi sağkalımla ilişkilidir^14,15. HER2 pozitif meme kanserlerinde neoadjuvan tedavide HER2 hedefleyici ajanlar kullanılmasa bile HER2 negatif hastalara göre daha iyi patolojik yanıt oranları vardır^16,17. Neoadjuvan tedavi ve cerrahi rezeksiyonun tamamlanmasından sonra pCR’nin elde edilmesi, hastalıksız sağkalımda iyileşme ile ilişkilidir. Bu korelasyon moleküler alt tipe bağlıdır ve triple negatif ve HER2 pozitif meme kanseri olan hastalarda belirgindir⁵.

Çalışmamızda HER2 pozitif meme kanserinde neoadjuvan kemoterapi sonrası patolojik yanıtı etkileyen faktörleri saptamayı amaçladık.

MATERIALS AND METHODS

From a total of 114 stage II and stage III breast cancer women with axillary lymph node involvement, who received neoadjuvant chemotherapy, 54 patients with HER2 expression positive were included. CerbB2 status was determined by immunohistochemical method from the biopsy material of the patients before neoadjuvant chemotherapy. Patients with cerbB2 negative status and 1+ were considered HER2 negative. HER2 expression was evaluated by fluorescent in situ hybridization method (FISH) from the tissues of patients with cerbB2 status of 2++, and those who were positive were considered HER2 positive. Patients with cerbB2 status of 3+++ were considered HER2 positive. Neoadjuvant chemotherapy regimen containing trastuzumab was given to all patients who were considered HER2 positive. Those with estrogen or progesterone receptor levels of ≥1% were considered hormone receptor positive, and those with both <1% were considered hormone receptor negative. Stage, tumor size and lymph node evaluation (TN) according to the American Joint Committee on Cancer (AJCC) TNM Staging Classification for breast cancer 8^th edition staging system including age, gender, tumor size, lymph node positivity and metastasis status of the patients and estrogen progesterone receptor status, Ki-67 proliferation index, tumor grade, menopausal status and pCR status after neoadjuvant treatment, neoadjuvant treatment regimen that was given, and histological subtype of the tumor were evaluated (Table 1).

Statistical Analysis

After testing the conformity of the data to the normal distribution, those showing normal distribution of continuous variables were analyzed with the t-test, and those that did not show normal distribution were analyzed with the Mann-Whitney U test. The χ² test was used in the analysis of categorical variables. All numerical data were expressed as mean values or ratios. For data that did not show normal distribution, comparisons between pre-post measurements were made using the Wilcoxon test.

Cox regression analysis was used to analyze univariate and multivariate data. Receiver operating characteristic (ROC) curve analysis was used to determine the Ki-67 cut-off value. Results were expressed as mean±standard deviation, median (lower limit and upper limit), number and percentage, and the value of p<0.05 was considered statistically significant. Statistical analysis of the data was performed using Statistical Package for the Social Sciences 21.0 software.

This article was approved by Çukurova University Faculty of Medicine Non-Invasive Clinical Research Ethics Committee with the decision number of 54 dated 10.06.2016.

RESULTS

Patient Characteristics

All of the patients participating in the study were women. A total of 114 patients who received neoadjuvant chemotherapy were evaluated. Twenty-eight (24.6%) patients were cerbB2 negative, 4 (3.5%) patients were cerbB2 1+, 35 (30.7%) patients were cerbB2 2++ and 47 (41.2%) patients were cerbB2 3+++. HER2 expression was detected by FISH method in 7 (6%) of 35 patients with CerbB2 2++. A total of 54 (47.3%) HER2 positive patients were evaluated. The median age of the patients included in the study was 52 years (age range: 34-76 years). The median Ki-67 score was 54% (range 5-90%), 20 (37%) patients had a Ki-67 score >50%, and 16 (29.6%) patients were hormone receptor negative. Approximately half of the patients had grade III tumors (n=28, 51.9%) and 29 (53.7%) patients were in the postmenopausal period. While docetaxel, carboplatin, trastuzumab (TCH) chemotherapy protocol was applied to 25 (46.3%) patients, dose-intensive Doxorubicin and cyclophosphamide/paclitaxel+trastuzumab chemotherapy protocol was applied to 23 (42.6%) patients. Reimbursement for pertuzumab was not available in our country at the time when the patient data were collected. Patients were offered this treatment option, but no patient accepted. Fourty-seven (87%) of the patients had stage III disease and approximately half had T4 tumor (n=25, 46.3%) while two-thirds had N2 (n=34, 63%) disease. When the histological subtypes of the tumors were examined, invasive ductal carcinoma was found in 40 (74.1%) patients.

Relationship Between Pathological Response and Clinicopathological Data

pCR was obtained in 30 (55.6%) of 54 patients. Clinicopathological data of the patients are shown in Table 1.

When the relationship between pCR and clinicopathological data was examined, no correlation was found among patients’ age, menopausal status, estrogen or progesterone receptor positivity, cerbB2 positivity, neoadjuvant chemotherapy protocols, N status and disease stage according to the TNM staging system, and histological subtype of the tumor (p>0.05). Higher rate of pCR was detected in the presence of grade III tumor, hormone receptor negativity, high Ki-67 score, and T3 or T4 tumors (p=0.036, p=0.033, p=0.021 and p=0.048, respectively) (Table 2). In the multivariate analysis performed to determine whether the variables associated with pCR were an independent risk factor, the presence of high tumor grade, negative hormone receptor and high Ki-67 score were found to be independent risk factors determining pCR after neoadjuvant therapy in HER2 positive breast cancer patients (p=0.043, p=0.047, p=0.035, respectively) (Table 3).

The most sensitive and specific values for study variables were determined using ROC curve analysis: The cut-off value for Ki-67 was 27.5% (Figure 1).

DISCUSSION

In our study, we aimed to investigate the factors affecting pCR in patients with HER2-positive breast cancer, and we found that hormone receptor negative, high Ki-67 score and the presence of high-grade tumor were independent risk factors affecting pCR.

Cortazar et al.¹⁶ evaluated 12 international studies on neoadjuvant therapy. They found that HER2 positive patient group had higher pCR than those with hormone receptor negative. In the study of Untch et al.¹⁸, although a higher pCR was shown in hormone receptor negative patients, the hormone receptor status was not statistically significant other than survival. In our study, we found that the hormone receptor negative group had a higher rate of pCR, and we revealed that hormone receptor negativeness was an independent risk factor determining pCR alone in patients with HER2-positive breast cancer (HR: 1,758, 95% CI: 0.758-2,214).

In another study by Cortazar and Geyer¹⁹, it was stated that pCR was lower with neoadjuvant therapy in patients with low-grade tumors. However, it was emphasized in the study that this group was a hormone receptor positive group. In the study of Jarzab et al.²⁰, tumor grade, Ki-67 and estrogen, and progesterone receptor negativity were determined as pCR-related tumor parameters. The highest chance of pCR was observed in patients with high grade tumor and Ki-67 ≥20%. Tumor grade and estrogen receptor status were predictive for pCR independent of other analyzed parameters. In the study of Spring et al.²¹, it was reported that higher pCR rates were observed in patients with grade 3 tumors. In the study of Karatas et al.²² in our country, no significant relationship was found between pCR and T status, but a significant relationship was found with grade. In our study, we found that a higher rate of pCR was obtained with neoadjuvant therapy in high-grade breast cancer patients independent of hormone receptor status as in the hormone receptor negative group, and tumor grade was an independent risk factor, similar to hormone receptor negativity [hazard ratio (HR): 2,321, 95% confidence interval (CI): 1,325-2,712].

In the study of Silva et al.²³, it was shown that patients with high Ki-67 proliferation index had a better response to neoadjuvant chemotherapy and had a higher rate of clinical complete response. In this study, the cut-off value for Ki-67 was taken as 14% (p=0.005). In the study, different cut-off values in Ki-67 expression were also examined and it was found that with increasing cut-off value for the predictive test, its sensitivity decreased and its specificity increased. In our study, we showed that a Ki-67 proliferation index higher than 27.5% would provide a higher rate of pCR after neoadjuvant therapy, and we found it to be an independent risk factor.

In the study of Untch et al.²⁴, in which they evaluated pCR with neoadjuvant therapy in HER2 positive breast cancer patients, no difference was found between patients with tumors larger than 4 cm and those with tumors smaller than 4 cm. In our study, although there was a statistically significant difference in univariate analysis between patients with T1 or T2 (≤5 cm) tumors and patients with T3 or T4 (>5 cm) tumors for pCR, it was not found to be an independent risk factor in multivariate analysis.

Study Limitations

The limitations of our study are the lack of pertuzumab use and the small number of patients. Further studies with more patients treated with new targeted agents are needed.

TARTIŞMA

Çalışmamızda HER2 pozitif meme kanserli hastalarda pCR’yi etkileyen faktörleri araştırmayı amaçladık ve hormon reseptörünün negatif oluşu, yüksek Ki-67 skoru ve yüksek grade’li tümör varlığının pCR’yi etkileyen bağımsız risk faktörleri olduğunu bulduk.

Cortazar ve ark.¹⁶ neoadjuvan tedavi ile ilgili 12 uluslararası çalışmayı değerlendirmiştir. HER2 pozitif hasta grubunun hormon reseptörü negatif olanlarının pozitif olanlara göre daha yüksek oranda pCR’ye ulaştığı saptanmıştır. Untch ve ark.’nın¹⁸ yapmış olduğu çalışmada da hormon reseptörü negatif hastalarda daha yüksek oranda pCR gösterilse de hormon reseptörü durumunun sağkalım dışında istatistiksel anlamı saptanmamıştır. Bizim çalışmamızda da hormon reseptörü negatif grubun daha yüksek oranda pCR’ye sahip olduğunu gördük ve hormon reseptörünün negatif olmasının HER2 pozitif meme kanserli hastalarda tek başına pCR’yi belirleyen bağımsız bir risk faktörü olduğunu saptadık [hazard ratio (HR): 1.758, %95 güven aralığı (CI): 0.758-2.214].

Cortazar ve Geyer’in¹⁹ yapmış olduğu bir başka çalışmada düşük grade’li tümöre sahip hastalarda neoadjuvan tedavi ile pCR’nin daha düşük oranda olduğu belirtilmiştir. Ancak çalışmada bu grubun hormon reseptörü pozitif grup olduğu vurgulanmıştır. Jarząb ve ark.’nın²⁰ çalışmasında tümör grade’i, Ki-67 ve östrojen, progesteron reseptör negatifliği pCR ile ilişkili tümör parametreleri olarak saptanmıştır. En yüksek pCR şansı, yüksek grade’li tümörü ve Ki-67 ≥%20 olan hastalarda gözlenmiştir. Tümör grade’i ve östrojen reseptör durumu diğer analiz edilen parametrelerden bağımsız olarak pCR için prediktif saptanmıştır. Spring ve ark.’nın²¹ yaptığı çalışmada grade 3 tümörlü hastalarda daha yüksek pCR oranları görüldüğü belirtilmiştir. Ülkemizde Karatas ve ark.’nın²² yaptığı çalışmada pCR ile T durumu arasında anlamlı ilişki saptanmamış, ancak grade ile anlamlı ilişki bulunmuştur. Bizim çalışmamızda hormon reseptörü negatif grupta olduğu gibi hormon reseptör durumundan bağımsız yüksek grade’li meme kanseri hastalarında neoadjuvan tedavi ile daha yüksek oranda pCR elde edildiğini ve hormon reseptör negatifliği gibi tümör grade’inin de bağımsız bir risk faktörü olduğunu saptadık (HR: 2.321, 95% CI: 1.325-2.712).

Silva ve ark.’nın²³yapmış olduğu çalışmada Ki-67 proliferasyon indeksi yüksek hastaların neoadjuvan kemoterapiden daha iyi yanıt aldığı ve daha yüksek oranda klinik komplet yanıt oranına sahip olduğu gösterilmiştir. Bu çalışmada Ki-67 için cut-off değeri %14 olarak alınmıştır (p=0,005). Çalışmada ayrıca Ki-67 ekspresyonunda değişik cut-off değerlerine bakılmış ve prediktif test için artan cut-off değeri ile sensitivitesinin azaldığı, spesifitesinin arttığı bulunmuştur. Biz çalışmamızda Ki-67 proliferasyon indeksinin %27,5’den yüksek olmasının neoadjuvan tedavi sonrası daha yüksek oranda pCR sağlayacağını gösterdik ve bağımsız bir risk faktörü olduğunu bulduk.

Untch ve ark.’nın²⁴ HER2 pozitif meme kanserli hastalarda neoadjuvan tedavi ile pCR’yi değerlendirdikleri çalışmada 4 cm üzerinde tümörü olan hastalarla 4 cm altında tümörü olan hastaların arasında bir fark saptanmamıştır. Çalışmamızda pCR için T1 veya T2 (≤5 cm) tümöre sahip hastalarla T3 veya T4 (>5 cm) tümöre sahip hastalar arasında tek değişkenli analizde istatistiksel anlamlı fark saptansa da çok değişkenli analizde bağımsız bir risk faktörü olmadığı görüldü.

Çalışmanın Kısıtlılıkları

Pertuzumab kullanılmaması ve hasta sayımızın az olması çalışmamızın kısıtlılıklarıdır. Yeni hedefe yönelik ajanlarla tedavi edilen ve daha fazla hastanın incelendiği çalışmalara ihtiyaç vardır.

CONCLUSION

Factors determining pCR after neoadjuvant therapy in HER2 positive breast cancer patients are Ki-67 proliferation index, tumor grade and hormone receptor negativity. Longer disease-free survival can be achieved by obtaining pCR with ideal neoadjuvant therapy in selected patient groups.

Ethics

Ethics Committee Approval: This article was approved by Çukurova University Faculty of Medicine Non-Invasive Clinical Research Ethics Committee with the decision number of 54 dated 10.06.2016.

Informed Consent: Retrospective study.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: A.E.Y., Concept: A.E.Y., S.P., Design: A.E.Y., S.P., Data Collection or Processing: A.E.Y., S.P., Analysis or Interpretation: A.E.Y., S.P., Literature Search: A.E.Y., S.P., Writing: A.E.Y., S.P.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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