CA : A Cancer Journal for Clinicians

Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) are commonly recommended anti-HER2 target agents by the U.S. Food and Drug Administration. This review summarizes the most significant and updated research on clinical scenarios related to HER2-positive breast cancer management in order to revise the guidelines of everyday clinical practices. In this article, we present the data on anti-HER2 clinical research of neoadjuvant, adjuvant, and metastatic studies from the past 2 decades. We also highlight some of the promising strategies that should be critically considered. Lastly, this review lists some of the ongoing clinical trials, findings of which may soon be available.

Targeted therapeutic options and future perspectives for HER2-positive breast cancer.

Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.

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Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms.

Metastasis accounts for 90% of breast cancer mortality. Despite the significant progress made over the past decade in cancer medicine our understanding of metastasis remains limited, therefore preventing and targeting metastasis is not yet possible. Breast cancer cells preferentially metastasize to specific organs, known as "organotropic metastasis", which is regulated by subtypes of breast cancer, host organ microenvironment, and cancer cells-organ interactions. The cross-talk between cancer cells and host organs facilitates the formation of the premetastatic niche and is augmented by factors released from cancer cells prior to the cancer cells' arrival at the host organ. Moreover, host microenvironment and specific organ structure influence metastatic niche formation and interactions between cancer cells and local resident cells, regulating the survival of cancer cells and formation of metastatic lesions. Understanding the molecular mechanisms of organotropic metastasis is essential for biomarker-based prediction and prognosis, development of innovative therapeutic strategy, and eventual improvement of patient outcomes. In this review, we summarize the molecular mechanisms of breast cancer organotropic metastasis by focusing on tumor cell molecular alterations, stemness features, and cross-talk with the host environment. In addition, we also update some new progresses on our understanding about genetic and epigenetic alterations, exosomes, microRNAs, circulating tumor cells and immune response in breast cancer organotropic metastasis.

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Organotropism: new insights into molecular mechanisms of breast cancer metastasis.

t BackgroundBackground Ductal carcinoma in situ (DCIS) of the breast is a disorder that has become moree common since it may manifest as microcalcifications that can be detected by screeningg mammography . Since selected women with invasive cancer can be treated safel yy with breast-conservatio n therapy it is paradoxical that total mastectomy has remainedd the standar d treatment for DCIS. We did a randomised phase III clinical trial too investigat e the role of radiotherapy after complet e local excision of DCIS. MethodsMethods Between 1986 and 1996, women with clinically or mammographicall y detectedd DCIS measuring less than or equal to 5 cm were treated by complet e local excisionn of the lesion and then randoml y assigned to either no further treatment (N=503)) or to radiotherapy (N=507. 50 Gy in five weeks to the whole breast) . The mediann duration of follow-up was 4.25 years (maximum 12.0). All analyses were by intentionn to treat. ResultsResults 502 patient s were followed up in the no further treatment group and 502 in the radiotherapyy group. In the no further treatment group 83 women had local recurrence s (444 recurrence s of DCIS. and 40 invasive breast cancer) . In the radiotherapy group 53 womenn had local recurrence s (29 recurrence s of DCIS, and 24 invasive breast cancer) . Thee 4-year local relapse-fre rate was 84/r in the group treated with local excision alone comparedd with 919f in the women treated by local excision plus radiotherapy (logrank P=0.005.. Hazard Ratio=0.62) . Similar reductions in the risk of invasive (40%. P=0.04) andd non-invasive (35%. P=0.06) local recurrence were seen. ConclusionsConclusions Radiotherap y after local excision for DCIS. as compared to local excision alone,, reduced the overal number of both invasive and non-invasive recurrence s in the ipsilaterall breast at a median follow-up of 4.25 years. RadiotherapyRadiotherapy in breast-conserving treatment for DCIS 33 33

[Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853].

// Qi Wu 1, * , Juanjuan Li 1, * , Shan Zhu 1 , Juan Wu 2 , Chuang Chen 1 , Qian Liu 1 , Wen Wei 1 , Yimin Zhang 1 , Shengrong Sun 1 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 2 Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China * These authors contributed equally to this work Correspondence to: Shengrong Sun, email: sun137@sina.com Yimin Zhang, email: dryiminzhang@163.com Keywords: breast cancer subtypes, distant metastases, SEER Received: November 01, 2016      Accepted: February 20, 2017      Published: March 02, 2017 ABSTRACT Background and Aims: This study aimed to access possible relationships between breast cancer subtypes and sites of distant metastasis in breast cancer. Results: A total of 243,896 patients, including 226,451 cases in control groups were identified. Bone metastasis was found in 8848 cases, compared with 1,000 brain metastasis cases, 3434 liver metastasis cases and 4167 lung metastasis cases. Patients with all subtypes were most prone to bone metastases, the incidence of bone metastasis in HR+/HER2+ subtype was up to 5.1 %. Further, HR−/HER2+ subtype patients had a higher probability of brain (OR = 1.978) metastasis compared to HR+/HER2− subtype patients. In addition, liver metastasis was more frequently observed in the HER2 positive subtypes compared with HER2 negative subtypes. Patients with TN primarily presented lung metastasis, but it made no difference in the probability of lung metastases of all subtypes. Materials and Methods: Using the 2010–2013 Surveillance, Epidemiology, and End Results Program(SEER) data, a retrospective, population-based cohort study to investigate tumor subtypes-specific differences in the sites of distant metastasis. Metastatic patterns information was provided for bone, brain, liver and lung. The breast cancer was classified into four subtypes: hormone receptor (HR) +/ human epidermal growth factor receptor 2 (HER2) −, HR+/HER2+, HR−/HER2+ and triple negative (TN). Conclusions: The pathological subtypes of breast cancer are clearly different in metastatic behavior with regard to the sites of distant metastasis, emphasizing that this knowledge may help to determine the appropriate strategy for follow-up and guide personalized medicine.

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Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study

The aim is to analyse the clinical presentation, treatment and outcomes in patients with Paget's disease with invasive ductal carcinoma (PD-IDC), with special emphasis on the role of surgical treatment. Using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2013, we investigated the differences in characteristics, overall survival (OS), and breast cancer-specific mortality (BCSM) between patients with PD-IDC and those with invasive ductal carcinoma (IDC). Compared with IDC group, patients with PD-IDC had a better prognosis and lower mortality in adjusted analyses. In the multivariate analysis of cases with PD-IDC, history of ALND was significantly associated with OS while Her2 status were associated with BCSM. Further, subgroup analysis demonstrated no difference between surgical treatment subgroups for either OS or BCSM. The results demonstrated that PD-IDC appears to alter the association between prognosis and Her2 status. Meanwhile, breast-conserving surgery with radiotherapy may be a feasible treatment alternative and sentinel lymph node biopsy should be considered as an appropriate treatment for patients with PD-IDC.

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Surgical treatment in Paget's disease with invasive ductal carcinoma: an observational study based on SEER.

// Qi Wu 1,* , Juanjuan Li 1* , Shan Zhu 1 , Juan Wu 2 , Xiang Li 3 , Qian Liu 1 , Wen Wei 1 and Shengrong Sun 1 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 2 Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 3 Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, Hubei, P. R. China * These authors contributed equally to this work Correspondence to: Shengrong Sun, email: // Keywords : breast cancer, male breast cancer, SEER data Received : May 31, 2016 Accepted : September 04, 2016 Published : September 15, 2016 Abstract Background & Aims: Substantial controversy exists regarding the differences in tumor subtypes between male breast cancer (MBC) and female breast cancer (FBC). This is the largest population-based study to compare MBC and FBC patients. Methods: Using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2012, a retrospective, population-based cohort study was conducted to investigate tumor subtype-specific differences in various characteristics, overall survival (OS) and breast cancer-specific mortality (BCSM) between males and females. Results: In all, 181,814 BC patients (1,516 male and 180,298 female) were eligible for this study. The male patients were more likely to be black, older, and have lower histological grades, more advanced stages, larger tumors, more lymph node and distant metastases and human epidermal growth factor receptor 2 (HER2)-negative tumors (each p <0.05). A matched analysis showed that the 2-year OS was 91.2% and 93.7% and that the BCSM was 2.2% and 2.5% for male and female patients, respectively. The univariate analysis showed that male triple-negative (TN), hormone receptor (HoR)-positive/HER2-positive and HoR-positive/HER2-negative patients had poorer OS ( p <0.01). Meanwhile, the HoR-positive/HER2-positive and TN subtypes were associated with a higher BCSM in MBC patients ( p <0.01). The multivariate analysis revealed that TN MBC patients had poorer OS and BCSM ( p <0.05). Simultaneously, the results showed that male patients in the HoR-positive/HER2-negative subgroup were less likely to die of BC when adjusting for other factors ( p <0.05). Conclusions: The analysis of 2-year OS and BCSM among the BC subtypes showed clear differences between MBC and FBC patients with the TN subtype; these differences warrant further investigation

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Poorer breast cancer survival outcomes in males than females might be attributable to tumor subtype

// Qi Wu 1 , Juanjuan Li 1 , Si Sun 2 , Shan Zhu 1 , Chuang Chen 1 , Juan Wu 3 , Qian Liu 1 , Wen Wei 1 and Shengrong Sun 1 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 2 Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 3 Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China Correspondence to: Shengrong Sun, email: // Keywords : breast carcinoma in situ, tumor subtype, treatment, outcomes Received : September 14, 2016 Accepted : November 23, 2016 Published : December 02, 2016 Abstract Background & Aims: To evaluate the clinical presentation, treatment and outcome of patients with breast carcinoma in situ (BCIS) with special emphasis on the role of the tumor subtype and local treatment in these patients. Methods: Using data obtained by the Surveillance, Epidemiology, and End Results (SEER) program from 2010-2013, a retrospective, population-based cohort study was conducted to investigate tumor subtype-specific differences in various characteristics, overall survival (OS) and breast cancer-specific mortality (BCSM). Results: In all, 6867 patients with BCIS were eligible during the 2010-2013 study period. Compared with the hormone receptor (HoR)+/HER- subgroup, patients with triple negative (TN) breast cancer were more likely to have tumors that were higher in grade and larger in size; they were also more likely to have tumors with ductal and comedo histology and were less likely to have tumors with cribriform and papillary histology (each P < 0.05). During the follow-up period, patients with TN breast cancer had an OS of 97.0% compared with 98.6 % in the HoR+/HER- subgroup ( P < 0.05). Furthermore, the BCSM rate was 1.0% for the TN group compared with 0.1% for the HoR+/HER- subgroup ( P < 0.05). Multivariate analysis revealed that patients with TN MBC had a poorer OS and BCSM ( P <0.05). Multivariate analysis of OS with respect to the local treatment history showed that patients who received breast-conserving surgery (BCS) combined with radiotherapy (R) were more likely to have an improved OS ( P < 0.05). Moreover, the results demonstrated that patients who underwent SLNB were more likely to have a lower BCSM ( P < 0.05). Conclusions: The results demonstrate that BCIS appears to alter the prognosis associated with the TN subtype. Meanwhile, BCS plus R was a preferable option and resulted in survival rates that were better than those achieved with mastectomy; thus, SLNB should be considered as an appropriate assessment of axillary staging in patients with BCIS.

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Breast carcinoma in situ : An observational study of tumor subtype, treatment and outcomes

// Qi Wu 1,* , Juanjuan Li 1,* , Si Sun 2 , Xiaoli Yao 1 , Shan Zhu 1 , Juan Wu 3 , Qian Liu 1 , Xiaojun Ding 1 , Manman Shi 1 , Kaiyang Li 4 and Shengrong Sun 1 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 2 Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 3 Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 4 Department of Electronic Science and Technology, School of Physics and Technology, Wuhan University, Wuhan, Hubei, P. R. China * These authors have contributed equally to this work Correspondence to: Shengrong Sun, email: // Keywords : thermal tomography, neoadjuvant chemotherapy, breast cancer Received : December 16, 2016 Accepted : March 15, 2017 Published : March 25, 2017 Abstract Background & Aims: This study aims to analyze the feasibility and predictive value of thermal tomography (TT) for monitoring early treatment response in patients with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy (NAC). Methods: Patients with LABC who were due to receive six cycles of NAC were examined by TT prior to NAC, the second cycle of NAC, the fourth cycle of NAC and surgery. Changes in TT parameters and ultrasonography were correlated with pathologic response to NAC, and the predictive value was assessed. Results: Forty-four patients were evaluable for response (25 pathologic responders and 19 nonresponders). As early as after the first cycle of NAC, changes in the TT parameters ΔTs, ΔTn, and ΔTa correlated significantly with pathologic response ( P < 0.05). The best predictor of pathologic response after the 6th cycle of NAC was TT (area under the receiver operating characteristic curve, 0.794), as opposed to cross-sectional areas and the longest diameter by ultrasonography. Conclusions: TT allows for monitoring early tumor response to NAC and can predict pathologic response in the early stages of therapy. Therefore, TT could be used as a novel imaging modality to monitor NAC treatment.

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Qian Liu

Papers

Breast cancer subtypes predict the preferential site of distant metastases: a SEER based study

Surgical treatment in Paget's disease with invasive ductal carcinoma: an observational study based on SEER.

Poorer breast cancer survival outcomes in males than females might be attributable to tumor subtype

Breast carcinoma in situ : An observational study of tumor subtype, treatment and outcomes

Thermal tomography for monitoring tumor response to neoadjuvant chemotherapy in women with locally advanced breast cancer.