Facilitating Breast-Conserving Surgery and Preventing Recurrence: Aromatase Inhibitors in the Neoadjuvant and Adjuvant Settings

Breast-conserving surgery (BCS) is an attractive option for many patients with early-stage breast cancer, because it provides a better cosmetic outcome than modified radical mastectomy, while reducing surgical morbidity. In patients with large, operable breast tumors who are ineligible for BCS, neoadjuvant therapy is a useful option for reducing the tumor size and for increasing the proportion of candidates for BCS. In patients with endocrine-responsive tumors, neoadjuvant endocrine therapy with either tamoxifen or an aromatase inhibitor (AI; anastrozole, letrozole, or exemestane) provides an alternative to neoadjuvant chemotherapy. Clinical trials have demonstrated the superiority of neoadjuvant AIs over tamoxifen in achieving a clinical response and increasing the frequency of BCS. In addition, adjuvant endocrine therapy with AIs, whether used as initial therapy instead of tamoxifen, in a switching strategy after 2–3 years of tamoxifen, or as extended adjuvant therapy after 5 years of adjuvant tamoxifen, has been shown in several randomized clinical trials to improve disease-free survival, reduce distant metastases and, in some cases, improve overall survival. The availability of the AIs for effective and well-tolerated neoadjuvant and/or adjuvant endocrine therapy represents an important advance in breast cancer treatment, and surgeons should be familiar with these new therapeutic options.     

Current and future role of neoadjuvant therapy for breast cancer

Neoadjuvant systemic chemotherapy is a possible therapeutic approach for the treatment of locally advanced operable, primarily non-operable or inflammatory breast cancer. Neoadjuvant systemic chemotherapy is an option for breast cancer patients who would require adjuvant chemotherapy otherwise based on clinical and histological examination and imaging. The use of neoadjuvant systemic therapy in operable breast cancer is currently increasing because of its advantages that include higher rates of breast conserving surgery and the possibility of measuring early in-vivo response to systemic treatment. The timing of axillary sentinel lymph node diagnosis (i.e. before or after neoadjuvant chemotherapy) is critical in that it may influence the likelihood of axillary preservation. It is not yet clear if neoadjuvant therapy might improve outcomes in certain subgroups of breast cancer patients. Neoadjuvant treatment modalities require a close collaboration between oncology professionals, including surgeons, gynecologists, medical oncologists, radiation oncologists, radiologists and pathologists. The most important parameter for treatment success and improved overall survival is the achievement of a pathologic complete response (pCR), although the role of pCR in patients with luminal A like tumours might be less informative. Identification of patient subgroups with high pCR rates may allow less invasive surgical or radiological interventions. Patients not achieving a pCR may be candidates for postoperative clinical trials exploring novel systemic treatments.     

Markers of increased risk for failure of adjuvant therapies

Mortality from breast cancer has been declining in the Western World since 1985. Arguably, widespread application of effective adjuvant systemic therapy has been a considerable contributing factor. Data from individual trials and the Oxford Overview Meta-analyses demonstrate that both endocrine and chemotherapy are associated with significant and substantive proportional reductions in annual hazard rates of relapse and death. These statistics raise the question: Should all patients be treated with all therapies in order to ensure an ongoing sharp decline in breast cancer mortality? The answer to this question depends on the perspectives of the patient, her caregiver, and her society towards the relative toxicities and benefits of therapy. If a patient is willing to accept toxicities for any benefit, then the answer is yes. However, if a woman is willing to forego some benefit to avoid the toxicities of therapy, then the clinician should carefully use well-validated prognostic and predictive factors to help the patient select her most acceptable treatment plan.     

Predicting response to systemic treatments: learning from the past to plan for the future

Therapeutic effects of adjuvant therapies for breast cancer have been assessed "across the board" and implemented using the principle that if a treatment is effective "on average" then it is effective "for all patients." Exploration and improved understanding of the biological basis for predicting response to available adjuvant therapies is essential to enhance patient care. As illustration, we consider the effects of chemotherapy and tamoxifen in two International Breast Cancer Study Group (IBCSG) trials for postmenopausal women. The level of estrogen receptor (ER) expression in the primary tumor is a powerful predictor of response to adjuvant therapy. Absence of ER identifies a chemosensitive cohort for which concurrent tamoxifen significantly blunts the large chemotherapy effect. High levels of ER expression are associated with good results using tamoxifen alone; adding chemotherapy provides little additional benefit. By contrast, adding chemotherapy to tamoxifen provides additional benefit for patients with node-positive disease and tumors expressing intermediate levels of ER. Identification of chemosensitive targets, e.g., absence of PgR, in tumors with intermediate ER expression is required to further tailor, adding chemotherapy within this otherwise endocrine-responsive cohort. Age is not a therapeutic target. Thus, the biological bases for treatment responsiveness must be defined. All findings from clinical trials and meta-analyses should be presented primarily according to steroid hormone receptor status and future studies should be designed as tailored treatment investigations.     

Neoadjuvant chemotherapy for locally advanced breast cancer results in alterations in preoperative tumor marker status

Neoadjuvant therapy followed by breast-conserving surgery has become an acceptable option for patients with locally advanced breast cancer. Although a distinct survival benefit has not been demonstrated using this approach, several questions have been raised following such therapy including its effects on receptor status and tumor markers. The current study retrospectively reviews estrogen receptor (ER), progesterone receptor (PR), and HER2-neu status in 55 consecutive patients treated by neoadjuvant chemotherapy. Preoperative and postoperative tumor markers were available for 43 of the 55 patients (78%). The pathologic complete tumor response rate (pCR) for this group was 19 per cent (8/43). Of those patients who did not achieve a pCR (n = 35), a change in tumor markers was seen in 25.7 per cent (9/35) of patients. When compared to a control group not undergoing neoadjuvant therapy, a significantly higher percent change in marker expression was noted in the neoadjuvant group (25.7% vs 5.9%, P = 0.046). ER, PR, and HER2-neu status remain important prognostic indicators for breast cancer. Tumor markers are useful in planning adjuvant therapy regimens. In this review, nearly 19 per cent of patients achieved a pCR. In patients not achieving a pCR, one in four patients had at least one change in tumor marker status. This study demonstrates the importance of establishing receptor and marker status prior to neoadjuvant therapy, as many patients will achieve a pCR and make tumor analysis impossible. Postoperative marker studies should be performed given the possibility of a change in status. The clinical relevance of this data will require further long-term follow-up. Until such data becomes available, caution should be considered when basing adjuvant therapy regimens on preoperative tumor marker studies alone.     

Predictors of complete pathological response after neoadjuvant systemic therapy for breast cancer

Background

The aim of the current study was to identify predictors of pathologic complete response (pCR) following neoadjuvant therapy.

Methods

From 2000 to 2007, 518 breast cancer patients received neoadjuvant therapy. Data were compared using χ² and Fisher's exact tests and multivariate analysis of variance, as appropriate.

Results

Of 518 breast cancer patients receiving neoadjuvant therapy, 81 (16%) had pCR (77 of 456 [17%] with chemotherapy, 4 of 62 [6%] with endocrine therapy; P < .05). Four factors were associated with pCR: higher tumor grade (P = .015), lack of estrogen receptor (ER) and progesterone receptor (PR) expression (P < .0001), HER2/neu amplification (P = .025), and negative lymph node status (P < .0001). On multivariate analysis, ER and PR negativity, HER2/neu amplification, and negative lymph node status were found to significantly correlate with pCR.

Conclusions

Patients with ER-negative and PR-negative and HER2/neu-amplified breast cancer phenotypes are more likely to experience pCR to neoadjuvant therapy. Although pCR is more frequently observed following neoadjuvant chemotherapy, it is rare following neoadjuvant endocrine therapy.     

Pathologic evaluation of response to neoadjuvant therapy drives treatment changes and improves long‐term outcomes for breast cancer patients

Systemic therapy for breast cancer may be given before (neoadjuvant) or after (adjuvant) surgery. When neoadjuvant systemic therapy is given, response to treatment can be evaluated. However, some prognostic information (for example, pathologic tumor size pretreatment) is then lost and pathologic evaluation of breast specimens after neoadjuvant therapy is more difficult. Pathologic complete response (pCR), defined as no invasive disease in the breast (ypT0/is or ypT0) and no disease in all sampled lymph nodes (ypN0), identifies patients with a lower risk of recurrence or death compared to those with residual disease. Multidisciplinary collaboration, marking of the tumor site and any lymph node involvement pretreatment, and access to specimen imaging to facilitate correlation of gross and microscopic findings are critical for accurate determination of pCR. For HER2‐positive and triple negative tumors requiring systemic therapy, giving the treatment before surgery identifies a high‐risk group of patients that can receive additional adjuvant therapy after surgery if a pCR is not achieved. Recent clinical trials have demonstrated that this approach reduced recurrence risk. More than ever, pathologic evaluation of response to neoadjuvant systemic therapy directs treatment received after surgery. Using a single standardized protocol for sampling of the post‐neoadjuvant surgical specimen allows pathologists to ensure accurate determination of pCR or residual disease and quantify residual disease. Residual cancer burden (RCB) and AJCC stage provide complementary quantitative information about residual disease and prognosis.     

2023年乳腺癌临床研究进展年终盘点

乳腺癌作为全球发病例数第一的恶性肿瘤,多年来一直是研究的热点。2023年,乳腺癌临床研究在局部治疗和系统治疗方面取得显著进展。在局部治疗方面,如何评估腋窝肿瘤负荷及选择合适的治疗手段是研究焦点。SOUND研究发现前哨淋巴结活检（SLNB）与无腋窝手术对于术前腋窝超声淋巴结阴性早期乳腺癌患者的5年无远处转移生存率相似,在术前超声对腋窝淋巴结筛查结果明确的情况下可避免SLNB。SENOMAC研究提供证据支持低负荷前哨淋巴结患者不进行腋窝淋巴结清扫（ALND）的可能性。OPBC05研究指出新辅助治疗后残留孤立肿瘤细胞（ITCs）的患者中ALND不改善长期生存,暗示豁免ALND的可行性。NSABP B-51研究显示,新辅助化疗（NAC）后腋窝淋巴结阴性（ypN0）患者的局部淋巴结放疗（RNI）并未显著改善主要研究终点。这些研究强调了个体化治疗方案的重要性,为乳腺癌的外科治疗和后续治疗提供重要指导。在系统治疗方面,早期激素受体阳性［HR（+）］乳腺癌治疗主要依赖手术、放疗及术后辅助内分泌治疗,但约30%的中高危患者仍面临复发和转移风险。MoHER2narchE和NATALEE研究证实了CDK4/6抑制剂（CDK4/6i）在早期HR（+）/人表皮生长因子受体2阴性［HER-2（-）］乳腺癌患者中的效果。此外,有关免疫治疗的研究,如KEYNOTE-756和CheckMate 7FL试验,探讨了PD-1单抗联合NAC在提高病理完全缓解（pCR）率和降低高危患者复发风险中的潜力。晚期HR（+）乳腺癌的标准治疗已从单一内分泌治疗发展为CDK4/6i联合内分泌治疗,但仍存在耐药问题,新型药物如ADC药物、PI3K/Akt/mTOR抑制剂正在被探索以提供更多治疗选项。TROPiCS-02和TROPION-Breast01研究验证了TROP2靶向ADC药物在治疗耐药HR（+）/HER-2（-）晚期乳腺癌患者中的有效性。同时,INAVO 120和Capitello-291研究突显了PI3K/Akt/mTOR信号通路抑制剂在提高治疗效果方面的潜力,尤其是对PIK3CA突变患者。在早期HER-2（+）乳腺癌治疗方面,PHERGain研究表明,基于¹⁸F-FDG PET/CT和根据pCR调整的降阶梯化疗在早期HER-2（+）乳腺癌新辅助治疗中有效。APTneo研究发现阿替利珠单抗联合化疗对新辅助治疗的pCR率提升有限,需进一步研究以优化疗效和安全性。在晚期HER-2（+）乳腺癌方面,PHILA和HER2CLIMB-02研究展示了TKI药物在一线和二线治疗中的有效性。DESTINY-Breast系列研究证明了德曲妥珠单抗（T-DXd）对HER-2（+）转移性乳腺癌各年龄段患者都有效且展现出良好的安全性。同时其对经治/稳定和未经治/活动性脑转移患者均有显著的疗效。早期三阴性乳腺癌（TNBC）的研究重点在于免疫治疗与化疗的联合应用,KEYNOTE-522研究显示化疗联合帕博利珠单抗的新辅助治疗及其作为后续辅助治疗显著提高了pCR率和无事件生存率,美国食品药品管理局和欧洲药物管理局已批准其用于高危早期TNBC的治疗。然而,IMpassion030研究表明,术后辅助免疫治疗可能并非所有早期TNBC患者的有效选项。对于晚期TNBC,KEYLYNK-009研究结果显示帕博利珠单抗联合PARP抑制剂奥拉帕利与帕博利珠单抗加化疗相比,并未显著改善预后,但在具有tBRCA突变的患者群体中,该联合疗法显著提高了中位无进展生存期（PFS）,表明其可作为这一患者群体的晚期一线维持治疗。BEGONIA研究的结果表明,Dato-DXd和度伐利尤单抗联合治疗显示出高反应率和较长的PFS,可能为晚期TNBC患者提供新的治疗选择。综上,2023年乳腺癌治疗领域的研究不仅在治疗方法上取得了突破,也在治疗理念上进行了革新,为乳腺癌患者带来了新的希望。     

老年乳腺癌术后辅助化疗对预后的影响

目的探讨老年乳腺癌的术后辅助化疗对预后的影响。方法收集80例Ⅰ~Ⅲ期≥65岁乳腺癌患者的资料,其中接受辅助化疗有47例,未接受辅助化疗有33例,分析两组的临床病理特点和预后特征。结果与未接受术后辅助化疗的患者比较,接受辅助化疗年龄轻的患者较多(P=0.005)、伴有合并症较少(P=0.040)、腋窝淋巴结转移率高(P0.001)、ER/PR阴性率高(P=0.029)、接受放疗概率高(P=0.005);而在肿瘤组织学分级、肿瘤大小、HER2表达、手术方式、内分泌治疗无明显区别(P0.05)。中位随访期为73个月,辅助化疗组与未辅助化疗组相比,无病生存率(DFS)无明显区别(78.7%vs 90.9%,P=0.147),总生存率(OS)也无明显区别(83.0%vs93.9%,P=0.098)。结论老年乳腺癌患者术后辅助化疗的获益不明显,但对于年纪较轻、伴有合并症较少且伴有腋窝淋巴结转移、ER/PR阴性等高风险因素的患者,应全面综合评估患者的耐受性和获益程度选择术后辅助化疗。     

Dose variation and regimen modification of adjuvant chemotherapy in daily practice affect survival of stage I-II and operable stage III Taiwanese breast cancer patients

To assess the effect of a non-standard dose and regimen of adjuvant chemotherapy on the clinical outcome in stage I–II and operable stage III Taiwanese breast cancer patients. Variables studied included treatment variation (regimen and dose of adjuvant therapy), lymph node status, tumor size, histologic grade, and hormone receptor status. Cox's multivariate regression analyses were used to select prognostic factors significant for disease-free survival (DFS) and overall survival (OS). In the multivariate analysis, lymph node-positive, a tumor size greater than 5 cm, grade III, hormone receptor-negative status, and non-standard adjuvant chemotherapy were independent prognostic factors for DFS and/or OS. Node-positive patients treated with standard adjuvant chemotherapy had a significantly better DFS (HR = 0.6; P = 0.032) and OS (HR = 0.54; P = 0.025) than those treated with non-standard adjuvant chemotherapy. Breast cancer patients receiving standard adjuvant chemotherapy have a better DFS and OS than those receiving non-standard adjuvant chemotherapy.     

Treatment of HER2-positive breast cancer

The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in ∼15% of breast cancer patients and was identified a quarter century ago as a marker of poor prognosis. By 1998, antibody therapy targeting the HER2 pathway was shown to demonstrably improve progression-free and overall survival in metastatic disease, and in 2005 evidence of improvement in disease-free and overall survival from the first generation of trastuzumab adjuvant trials became available. However, not all patients with HER2 overexpression benefit from trastuzumab. Second-generation studies in metastatic disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase inhibitors such as lapatinib, new HER2/HER3 antibodies such as pertuzumab, and the new antibody chemotherapy conjugate ado-trastuzumab emtansine. These successes supported the launch of second-generation adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or sequentially with chemotherapy that will soon complete accrual. HER2-positive breast cancer in the setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given preoperatively may allow an earlier assessment of their clinical benefit in the adjuvant setting. An adjuvant trial of trastuzumab in patient whose tumors express normal levels of HER2 and trials of single/dual HER2-targeting without chemotherapy are also ongoing. In this article, we review the current data on the therapeutic management of HER2-positive breast cancer.     

Oophorectomy in Breast Cancer—Controversies and Current Status

The role of oophorectomy in the treatment of breast cancer is known for over 100 years. Ovarian ablation has a relatively large positive effect on both disease-free survival (DFS) and overall survival (OS) in premenopausal women when compared to no adjuvant treatment. Today the standard of care in adjuvant therapy of endocrine responsive tumors in premenopausal women is tamoxifen with or without chemotherapy. The role of oophorectomy /ovarian ablation in current surgical practice is discussed and important issues highlighted in the article.     

乳腺癌分子亚型在预测新辅助化疗疗效及患者预后中的作用

目的 本研究旨在探讨乳腺癌的分子亚型与乳腺癌的病理完全缓解及患者预后的关系.方法 收集2007年1月-2010年1月在芜湖市第二人民医院接受新辅助治疗的101例乳腺癌患者的病例资料,按照ER、PR及Her-2的免疫组化的结果将其分为4型,单因素与多因素分析临床病理因素与病理完全缓解的关系.结果 19例(18.8％)患者取得病理完全缓解,三阴性乳腺癌是病理完全缓解的独立预测因素(OR=3.35,95％CI:1.25 ～ 9.79,P=0.012),而Her-2丰富型乳腺癌相比较于luminal A型乳腺癌则取得更高的病理完全缓解率(OR =3.11,95％CI:1.09 ～ 10.89,P=0.021).而病理缓解率与无病生存率密切相关(P =0.002).但三阴性乳腺癌的总生存期和无病生存期更短(P =0.008,P=0.0006).结论 三阴性乳腺癌和Her-2丰富型乳腺癌较luminal A型乳腺癌更容易获得新辅助化疗后的病理完全缓解,但三阴性乳腺癌的预后仍然较差,可能与其在治疗后仍有肿瘤残留有关.     

Adjuvant treatment of elderly breast cancer patients

Increasing age is the major risk factor for breast cancer. About half of all new breast cancers and more than half of breast cancer deaths in affluent nations occur in women 65 years and older. Endocrine therapy with aromatase inhibitors or tamoxifen is appropriate adjuvant therapy for older women with life expectancies of greater than 5 years and hormone receptor positive tumors. The greatest benefit of adjuvant chemotherapy is in elders with hormone receptor negative, node positive, or high-risk node negative tumors. The effect of co-morbidity on survival must be factored into all adjuvant therapy decisions and newer validated tools can accurately estimate non-breast cancer related survival. Age bias still exists and results in frequent undertreatment of older women and compromised survival. Elders remain under-represented in clinical trials and should be encouraged to participate. Health care providers as well as government leaders and patients need to be educated on cancer in elders.     

Preoperative concurrent chemo- and endocrine therapies for women with large operable breast cancer expressing steroid hormone receptors

Preoperative chemotherapy and endocrine therapy yielded low pathological complete remission (pCR) rates in patients with endocrine responsive breast cancer. Patients with large operable (cT2–T3, N0–2, M0), ER ≥10% breast cancer were treated in two consecutive studies with preoperative chemotherapy (Study I: six courses of either fluorouracil, leucovorin, vinorelbine (FLN), or vinorelbine, cisplatin, and continuous infusion of fluorouracil (ViFuP), at the discretion of the treating physician; Study II: capecitabine and oral vinorelbine (CAVINO)). Concurrent letrozole (in association with triptorelin if premenopause) was given. Sixty-five (58 evaluable) and 55 (all evaluable) patients were enrolled in the two studies. In Study I there were 43 objective responders (74%, 95% CI 63–85%), three of whom had pCR. Thirty-nine objective responses (91%) and all pCR were observed in patients with tumors expressing ER ≥50%. In Study II 34 patients (62%, 95% CI 49–75%) had an objective response. Endocrine therapy administered together with new intravenous, containing regimens should be explored in the preoperative treatment of endocrine responsive breast cancer.     

Neo-adjuvant hormonal therapy

Abstract:  Neo-adjuvant endocrine therapy has opened new alternatives for locally advanced breast cancer. Such therapy, which has permitted us to expand the treatment role of neo-adjuvant therapies, may be of great benefit to patient groups such as the elderly, those not suited for chemotherapy, and those whose response may not be optimal. This therapy also may be able to help us identify agents that could improve outcomes in the adjuvant setting as well as possible biologic predictors for outcome. The latest generation of endocrine therapy for breast cancer, aromatase inhibitors, has proved superior to tamoxifen in terms of toxicity and efficacy in the adjuvant setting and is currently being studied in other clinical trials. Current findings indicate that these agents are less toxic and better tolerated than neo-adjuvant chemotherapy and that third-generation anti-hormomal therapy offers improved tumor response compared with tamoxifen, which has resulted in increased breast conserving surgery. Biomarker findings of improved response in tumors that are both estrogen receptor positive and HER-2 positive as well as progesterone receptor positivity only will be important for planning future selective treatment and clinical trials.     

Axillary lymph node status,but not tumor size,predicts locoregional recurrence and overall survival after mastectomy for breast cancer

OBJECTIVE: To assess the significance of axillary lymph node status and tumor size for predicting locoregional recurrence (LRR) and overall survival after mastectomy for breast cancer and to discuss the utility of postmastectomy radiation therapy. SUMMARY BACKGROUND DATA: Patients with locally advanced breast cancer require multimodality treatment combining chemotherapy (and/or hormonal therapy), surgery, and radiation. Randomized trials have demonstrated that postmastectomy radiation reduces LRR, but no overall survival benefit has been established. METHODS: Criteria for accrual to the Alabama Breast Cancer Project (1975-1978) were female gender and T2-3 breast cancer with M0 status. Patients underwent a radical or a modified radical mastectomy. Node-positive patients received adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy or adjuvant melphalan. Patients were evaluated for LRR and overall survival based on the number of positive axillary lymph nodes and (in N0 patients) pathologic tumor size. Significance was determined using chi-square analysis. Survival curves were generated using the Kaplan-Meier method and were compared by log-rank analysis. RESULTS: After median follow-up of 15 years, neither type of surgery nor chemotherapy was shown to affect locoregional disease-free or overall survival. LRR rates were higher and overall survival rates were lower in patients with nodal involvement, while tumor size was not shown to significantly affect these rates. CONCLUSIONS: Patients with axillary lymph node metastases may benefit from postmastectomy radiation, but the use of postmastectomy radiation in N0 patients is not supported when it is based on tumor size alone.     

Neoadjuvant Therapy – What Have We Achieved in the Last 20 Years?

Neoadjuvant chemotherapy is the standard of care for patients with large, inoperable tumors or inflammatory breast cancer, but it is also increasingly considered for women with operable disease. Several randomized trials have demonstrated that anthracycline- and taxane-containing regimens in operable breast cancer were equally effective in terms of disease-free or overall survival regardless of whether they were administered postoperatively or preoperatively. Further neoadjuvant treatment allows for a higher rate of breast conserving surgery. Tumor responses in terms of pathologic complete remission after short-term chemotherapy will probably only serve as a surrogate marker for long-term outcome in some molecular breast cancer subtypes like the triple-negative, HER2-positive, and some luminal B subsets. Recent trials showed that in HER2-positive disease pCR rates were as high as 70% when 2 HER2-targeted agents were added to chemotherapy.