Metastatic disease of the breast and local recurrence of breast cancer

Breast cancer is a major health problem worldwide with over one million new cases diagnosed each year. The aim of treatment is to achieve good loco-regional control, provide appropriate adjuvant therapy and treat potential micro-metastasis. Good loco-regional control is essential to minimize local recurrence rates with histological clear margin being the most important factor. Several prognostic factors can be used to guide suitable adjuvant therapy. The most important is hormone sensitivity and the use of hormone manipulation has improved both recurrence rates and overall survival. Early detection with breast screening and better treatment options have improved outcome, but still 35–40% of patients will eventually present with metastatic disease. Metastatic disease is incurable, but several therapies have been shown to maintain a good quality of life whilst prolonging survival. A multidisciplinary team approach is essential to obtain the diagnosis and plan the appropriate treatment. The diagnosis of metastatic disease brings distress to patients and their relatives and support should be available from palliative care teams.     

Metastatic disease of the breast and local recurrence

Multimodality primary therapies for breast cancer combined with earlier detection have led to a sharp decline in the death rate from breast cancer in the UK over the last 40 years in the face of a rising incidence. The latest UK statistics from Cancer Research UK report 55,122 new cases of breast cancer in 2015 with 11,563 deaths from breast cancer recorded in 2016. Crudely, this equates to a cure rate of around 80% for all comers and demonstrates a clear improvement in outcome with 50,285 new cases in 2011 and 11,716 deaths in 2012. Despite this good news, there are still significant numbers of women (and men) who suffer from either a local recurrence or metastatic disease following apparently successful treatment for early breast cancer (Stage I to III). Only a minority of individuals, 6.6% with the stage recorded at diagnosis, present with stage IV disease. This review considers the treatment options available to individuals with locally recurrent and advanced breast cancer (ABC).     

Metastatic disease of the breast and local recurrence

Multimodality primary therapies for breast cancer combined with earlier detection have led to a sharp decline in the death rate from breast cancer in the UK over the last 40 years in the face of a rising incidence. The latest UK statistics from Cancer Research UK report 50,285 new cases of breast cancer in 2011 with 11,716 deaths from breast cancer recorded in 2012. Crudely, this equates to a cure rate in excess of 75% for all comers. Despite this good news, there are still significant numbers of women (and men) who suffer from either a local recurrence or metastatic disease following apparently successful treatment for early breast cancer (Stage I–III). Only a minority of individuals, 6.6% with the stage recorded at diagnosis, present with stage IV disease. This review considers the treatment options available to individuals with locally recurrent and advanced breast cancer (ABC).     

Treatment of locally recurrent and advanced breast cancer

The incidence of breast cancer in the UK continues to increase; however, the death rates continue to decline. Mortality rates have reduced by 19% in the UK in the last decade and are projected to fall by a further 26% in 2014–2035. Cancer research UK reports 55,176 new cases in 2015–2017 with 11,547 deaths from breast cancer reported from 2016 to 2018. Ten-year survival for all comers is reported at 76%. Largely, the improvements in outcomes is felt to be multi factorial in nature with earlier detection of cancers, increased axial imaging and the rapidly progressing and expanding radiotherapy and systemic therapy treatment options available. Irrespective of this, there are still a number of patients diagnosed with more advanced disease. Between 13% and 21% of patients are diagnosed with stage III/IV disease, with 7% of patients having metastatic disease at diagnosis. The following review discusses the treatment options available to patients with locally recurrent or metastatic breast cancer (MBC).     

Prognosis of patients with local recurrence after mastectomy or conservative surgery for early-stage invasive breast cancer

Between 1983 and 1987, 1309 women with stage I or II breast cancer underwent mastectomy (n=894) or conservative surgery (CS, n=415). Of these patients, 124 developed an isolated local recurrence (ILR): chest wall, 56 and in-breast, 68. The 10-year actuarial rate of cause-specific survival after treatment for ILR was 52%. On multivariate analysis three independent prognostic factors for the risk of death after ILR were identified: operability of recurrence (operable vs. inoperable, relative risk [RR]: 5.9), age at initial diagnosis (>40 vs. 40 years, RR: 2.2) and time to ILR (>24 vs. 24 months, RR: 2). Initial lymph node stage (negative vs. positive) showed borderline significance (p=0.06), and type of initial surgery (CS vs. mastectomy) and recurrent tumor grade (1–2 vs. 3) were not independent predictors of survival. In the mastectomy group, single surgical scar recurrence with initial node negative stage predicted good prognosis, and the 10-year survival was 85%. In the CS group, the 10-year survival rate was 88% with new primary tumor and 54% with true recurrence (p=0.01), and the type of salvage surgery (mastectomy vs. repeat complete excision) had no significant impact on survival (p=0.2). The majority (n=44) of CS patients developed 2 cm in-breast recurrence, and the 10-year survival was 81% after both salvage excision (n=28) and mastectomy (n=16). The identified unfavorable prognostic factors are pointers of the forthcoming systemic progression. Patients with 2 cm in-breast recurrence might receive a second CS.     

Locoregional recurrence in patients with HER2 positive breast cancer

Literature shows that HER2/neu positive breast cancer cells are more sensitive to radiation-induced apoptosis by targeting the epidermal growth factor receptor family tyrosine kinase. We selected 466 patients with pT1-2 HER2/neu positive tumors who received adjuvant trastuzumab for primary invasive breast cancer. Patients were divided into three groups [Quadrantectomy followed by conventional radiotherapy vs Quadrantectomy followed by Intra-operative radiotherapy with electrons vs Mastectomy without radiotherapy]. After a median follow-up of 52 months, the 5-year cumulative incidence of locoregional recurrence (LRR) was 1.9%, 11.5% and 5.0% respectively (p < 0.01). At the multivariate analysis, extensive perivascular invasion, Luminal B HER2/Progesterone Receptor (PgR) negative status and Quadrantectomy followed by Intra-operative radiotherapy with electrons have significantly increased the risk of LRR. Our results suggest that HER2/neu positive breast cancer might have better outcomes when treated simultaneously with external radiotherapy and trastuzumab. Moreover, we underline the importance of PgR and further new stratification of risk among luminal subtypes.     

Factors associated with local breast cancer recurrence after lumpectomy alone

Background: The purpose was to determine the rate of local breast relapse in patients with breast cancer uniformly treated with partial mastectomy but without postoperative radiotherapy and without systemic adjuvant therapy. We also systematically examined the factors associated with local recurrence to determine whether a low-risk subgroup existed. Methods: A retrospective review of a prospectively followed (median, 8 years) cohort of 293 patients was performed. The end-point was ipsilateral local breast cancer recurrence. The patient's age, tumor size, nodal status, estrogen and progesterone receptor status, histology, and tumor and nuclear grade were studied, as were the presence and amount of carcinoma in situ and the presence of tumor emboli using univariate Kaplan-Meier and Cox step-wise multivariate analyses. Results: The overall local relapse rate was 26% (77 recurrences). Univariate factors significantly associated with decreased local relapse included older age, negative nodes, small tumor size, positive estrogen receptor status, and absence of tumor emboli. Significant multivariate variables were age, nodal status, estrogen receptor status, absence of comedo carcinoma in situ, and tumor emboli. A low-risk subgroup of 66 patients was defined with a 6% 10-year local recurrence rate. Conclusion: Important patient and tumor variables associated with local breast cancer relapse after breast-conserving surgery can define a low-risk subgroup.     

乳腺癌术后局部复发的治疗及预后分析

目的 探讨乳腺癌术后局部复发的治疗方案及影响预后的相关因素.方法回顾性分析天津肿瘤医院2002年7月至2005年2月期间收治的477例乳腺癌术后复发患者的临床资料.结果 477例复发病例中,术后1年内复发占26.2%(125/477),2年内复发占61.2%(292/477).局部复发后远处转移率为65.0%(310/477),复发后5年总生存率48.4%.不同复发部位、临床分型、有无放射治疗、放射治疗范围、有无手术切除或切除活检的亚组之间局部控制率的差异有统计学意义(P<0.05).不同原发肿瘤分期、无病间期、临床分型以及治疗方式的亚组间远处转移率及5年总生存率的差异有统计学意义(P<0.05),多因素分析显示治疗方案单一、原发肿瘤分期晚、三阴型乳腺癌是影响复发性乳腺癌预后的独立危险因素(P<0.05).结论 多部位复发者和三阴型乳腺癌局部控制不佳,局部扩大野放射治疗结合手术治疗是改善局部控制率的必要模式.原发肿瘤分期晚、2年内复发、三阴型的乳腺癌复发后容易发生远处转移,对于复发性乳腺癌采取综合治疗方案可以提高患者的生存率.

Abstract：

Objective To explore an optimal treatment and to study the prognosis related factors of breast cancer patients with local recurrence after mastectomy. Methods From 2002. 7 to 2005. 2, 477female patients with loco-regional recurrence of breast cancer treated in Tianjin Cancer Hospital were analyzed retrospectively. Results In 477 cases, recurrence within 1 year after mastectomy accounted for 26. 2% , recurrence within 2 years accounted for 61. 2%. There were 310 cases with metastasis after local recurrence was diagnosed, accounting for 65.0%. 5-year total survival rate after recurrence is 48.4%.Local control rates varied in subgroups with different recurrence site, clinical subtypes, radiotherapy fields,with or without radiotherapy, surgical resection or excisional biopsy ( P<0. 05 ). There was a statistical difference in distant metastasis rate and 5-year survival rate among subgroups which had different clinical stage of primary tumor, disease-free interval, clinical subtypes or treatment methods ( P<0. 05 ). Simplistic treatment option, late clinical stage of primary tumor and triple-negative breast cancer were the independent factors predicting poor prognosis for recurrent breast cancer ( P<0.05 ). Conclusions Multi-site recurrence and triple-negative breast cancer lead to a poor local control. Local expansion of radiotherapy combined with surgery improves the local control rate. Patients with late clinical stage of primary tumor,recurrence within 2 years, triple-negative breast cancer are likely to have distant metastasis when recurrence is diagnosed. Combined treatment program improves survival rate.     

Time to First Tumor Progression as Outcome Predictor of a Second Trasuzumab‐Based Therapy beyond Progression in HER‐2 Positive Metastatic Breast Cancer1

Abstract: In a previous analysis performed on a cohort of 37 HER‐2 positive metastatic breast cancer (MBC) patients treated with trastuzumab beyond progression, we found that a second trastuzumab‐based therapy is associated with a considerable response rate and preserved time to progression as compared with a first trastuzumab‐based therapy. In the present study, we extended the analysis to a total of 69 patients treated in four different italian Institutions, also trying to identify clinical predictors of sensitivity to a second trastuzumab‐based therapy beyond progression. Efficacy results on the overall population confirmed that a second trastuzumab‐based therapy beyond progression is an active regimen (27.5% of responses and 6.5 months of time to progression, respectively). Median time to progression to the first trastuzumab therapy (TTP1) identified two groups of patients with different sensitivity to trastuzumab beyond progression (group A, TTP1 ≥ 8 months and group B, TTP1 < 8 months) in terms of time to second progression and post‐progression survival (group A versus group B showed respectively a time to second progression of 7.6 versus 4.7 months, p = 0.05, and a post‐progression survival of 31.7 months versus 21.8 months, p = 0.04). In the multivariate analysis, only TTP1 was a predictor of time to second progression and post‐progression survival. Despite the recent approval of lapatinib plus capecitabine for trastuzumab‐progressing patients, it is still reasonable to offer trastuzumab beyond progression to HER‐2 positive MBC patients, because these data confirm the potential utility of such a conduct. In the clinic, time to first tumor progression may represent a useful tool to identify patients who are more likely to benefit from trastuzumab beyond progression.     

Factors associated with local breast cancer recurrence after lumpectomy alone: Postmenopausal patients

Background: We have been following a cohort of patients who underwent a lumpectomy without receiving adjuvant radiotherapy or adjuvant systemic therapy. We now report the experience of a postmenopausal subgroup. Methods: The postmenopausal subgroup included 244 patients accrued between 1977 and 1986 and followed up. The end point was ipsilateral local breast cancer recurrence. The factors studied were the patient’s age in years; tumor size (in mm); nodal status (N-, Nx, N+); estrogen and progesterone receptor status (<10, ≥10 fmol/mg protein); presence or absence of lymphovascular/perineural invasion; presence or absence, and type, of DCIS (none, non-comedo, comedo); percentage of DCIS; histological grade (1,2,3); and nuclear grade (1,2,3). Univariate analyses consisted of Kaplan-Meier plots and the Wilcoxon (Peto-Prentice) test statistic; the multivariate analyses were step-wise Cox and log-normal regressions. Results: The median follow-up of those patients still alive was 9.1 years, and the overall relapse rate was 24% (59/244). The univariate results indicated that the characteristics of smaller tumor size, negative nodes, positive ER status, and no lymphovascular or perineural invasion were associated with significantly (P<.05) lower relapse. From the multivariate analyses, the factors lymphovascular or perineural invasion, age, and amount of DCIS were all significantly associated with local relapse with both Cox and log-normal regressions. Additionally, there was weak evidence of an association between ER (P=.08 in the Cox regression and in the log-normal) and nodal status (P=.09 in the log-normal regression) with local relapse. We also are able to define a low-risk subgroup (N-, age ≥65, no comedo, ER positive, no emboli) with a crude 10-year local recurrence rate of 9%. Conclusion: With longer follow-up, and for postmenopausal patients, there continues to be support for the theory that local relapse is affected by the factors lymphovascular or perineural invasion, age, amount of DCIS, ER, and nodal status. A low risk subgroup has been identified. Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, March 16–19, 2000, New Orleans.     

直肠癌根治术后局部复发的因素和预防要点

直肠癌根治术后局部复发已引起临床广泛关注并成为研究难点。影响直肠癌术后局部复发因素较多,但主要有肿瘤远切缘、环周切缘肿瘤浸润程度、直肠系膜切除范围,肿瘤组织分化程度,临床肿瘤TNM分期,手术方式选择等。重视手术操作规范,合理选择手术方式,术中确保远近切缘及环周切缘阴性,坚持全直肠系膜切除（TME）原则,给予新辅助放化疗等综合治疗是预防直肠癌术后复发的关键。     

Scientific Presentation Award. Patterns of local breast cancer recurrence after skin-sparing mastectomy and immediate breast reconstruction

BACKGROUND: Local recurrence rates after skin-sparing mastectomy and immediate reconstruction are similar to recurrence rates after conventional mastectomy. We investigated the pattern of local recurrences and risk factors associated with them. METHODS: We identified 206 patients who underwent 210 skin-sparing mastectomies with immediate reconstruction from 1998 to 2006 in our database. RESULTS: Eleven patients had local recurrences (5.3%). Nine developed in the quadrant of the corresponding primary tumor. There were no significant differences between patients who recurred and those who did not with respect to tumor size/stage, margin status, estrogen receptor/progesterone receptor/Her2neu status, lymph node metastases, or radiation therapy (P > .05). Patients with grade 3 invasive tumors or high-grade ductal carcinoma in situ were more likely to recur than patients with grade 1 or 2 invasive tumors or low- or intermediate-grade ductal carcinoma in situ (P = .0035). Those patients who recurred had a significantly decreased overall survival compared to patients who did not recur (P = .0006). CONCLUSIONS: Skin-sparing mastectomy and immediate reconstruction has a low local recurrence rate. Recurrences occur most commonly in the same quadrant as the primary tumor and treatment approaches include surgery, chemotherapy, and radiation therapy. Local recurrence portends a poorer overall survival.     

The nature of local recurrence after colorectal cancer resection

Objective Local recurrence (LR) after rectal cancer resection has long been regarded as a particular problem, its incidence having been high. This study aims to determine the reasons why. Method A prospective record was kept of all 887 cases of colorectal adenocarcinoma referred to one surgeon between 1989 and 2000. Of these, 802 underwent major resection. They were followed up for 5 years or until death. Results There was no significant difference between LR rates throughout the colorectum (P = 0.74). LR was significantly related to tumour grade (P < 0.001) and to tumour stage (P < 0.001), but not to the need to resect involved adjacent structures (P = 0.08), nor, after restorative rectal resection, to the distal margin of clearance (P = 0.97). A difference became apparent between recurrence resulting from tumour left in or implanted into the operation field and tumour resulting from pre‐excision metastasis, here called, respectively, technique‐related (TLR) and pre‐excision metastatic (MLR) local recurrence. MLR was significantly related to tumour stage (P < 0.001), while TLR was not. Some TLR can be curatively excised. Conclusion Rectal LR is no more common than colonic LR. There may be practical merit in discriminating between TLR and MLR.     

Routine screening for local recurrence following breast-conserving therapy for cancer with dynamic contrast-enhanced magnetic resonance imaging of the breast

Background: Dynamic contrast-enhanced magnetic resonance imaging (MRI) of the breast is highly sensitive for the diagnosis of primary breast malignancy. We investigated the clinical application of dedicated dynamic breast MR for routine screening for local recurrence following breast-conserving therapy. Methods: Patients underwent a single dynamic MR of the breast routinely in the period 1 to 2 years following treatment, or earlier if recurrence was suspected. A biopsy was performed if there was suspicion of recurrence on MR. Results: One hundred and five patients with a median age of 58 years (range 50 to 65 years) were recruited for the study. Sixteen biopsies were performed and nine recurrences were confirmed histologically. Patients not undergoing biopsy have been followed up for a median of 341 days (range 168 to 451 days) following the MR. The sensitivity for clinical examination, mammography, examination combined with mammography, and MRI alone for the detection of recurrent cancer were 89%, 67%, 100%, and 100%, respectively, and the specificity was 76%, 85%, 67%, and 93%. Conclusion: Combined clinical examination and mammography are as sensitive as dedicated dynamic MR of the breast for the detection of locoregional recurrence, but breast MRI is associated with a far greater specificity. Therefore, dedicated dynamic breast MRI should be used when there is clinical or mammographic suspicion of recurrence to confirm or refute its presence.Presented at the 50th Annual Cancer Symposium of The Society of Surgical Oncology, Chicago, Illinois, March 20–23, 1997.     

Prevention of local recurrence by extended lymphadenectomy for rectal cancer

This study was undertaken to determine if the degree of lymphadenectomy correlates with the prevention of local recurrence. The authors retrospectively reviewed the clinical data of 269 patients who underwent curative surgery for rectal cancer. The study was divided into three periods based on the method of lymphadenectomy as follows: period I (1963–1979) when extended lymphadenectomy was not performed; period II (1980–1985) when this was partially done with no attempt to dissect the obturator and proximal middle rectal lymph nodes; and period III (1986–1990) when this was completely performed for patients with appropriate indications. The local recurrence rates were 21%, 10%, and 8% for Periods I, II, and III, respectively (P<0.05). The incidence of local recurrence tended to be greater in period I versus periods II and III according to type of operation, location, and stage of the primary tumors. The local recurrence rates arising from lateral node metastases were 11%, 4%, and 2% for periods I, II, and III, respectively (P<0.05), while the incidence related to an insufficient surgical margin was approximately 5% throughout the three periods. We thus conclude that the degree of lymphadenectomy is a major determinant of local recurrence following a curative operation for rectal cancer.     

Clinical characteristics of women presenting with skin-only recurrence of breast cancer

Background

Locoregional failure after breast cancer treatment is usually heralded as a significant risk factor for systemic recurrence. However, locoregional recurrence may have different presentations, some of which may represent a more benign course. An example of this is the phenomenon of isolated chest wall recurrence (CWR). Given the paucity of data describing the clinical outcomes of women who recur this way, we sought to review the natural history and prognosis of patients presenting with this specific presentation.

Methods

Women who previously underwent primary treatment for breast cancer and subsequently developed an isolated CWR were identified. Histologic and treatment data as it related to their primary diagnosis and demographic data were obtained by chart review. Modalities of treatment for isolated CWR were also collected.

Results

We identified 17 patients who experienced an isolated CWR from January 1987 to May 2005. The median age at original diagnosis was 61 years (range 33-94 years). Median time to isolated CWR was 20 months (range 6-134). Eleven patients were treated with primary resection, 12 with radiotherapy, and 3 with a combination of hyperthermia and electron beam radiation. Ten patients went on to receive endocrine therapy, 6 received chemotherapy, and 2 were observed. Ten of these patients (58%) experienced a second event and for this group the median time to second event was 24 months (range 8-109). Median overall survival was 80 months (range 3-134) for the entire cohort.

Conclusions

Patients experiencing a chest wall recurrence may have a benign course suggesting this may be an indolent presentation of local regional recurrence. The proper therapy of these patients may require further study.     

Reresection for local recurrence of rectal cancer

(Received for publication on Aug. 10, 1998; accepted on Mar. 11, 1999)     

Surgery for local recurrence of rectal cancer

OBJECTIVE: Despite improvement in management of primary rectal cancer, 2.6-32% of patients develop local recurrence. A proportion of these patients can be amenable to salvage surgery. The present article reviews the evidence for and against the surgical management for local recurrence of rectal cancer, the role of adjuvant and intraoperative radiotherapy (IORT), and evaluates short and long-term outcomes. METHOD: A literature search was performed using Medline, Embase, Ovid and Cochrane database for studies between 1980 and 2005 assessing surgical management of local recurrence of rectal cancer and the evidence was critically evaluated. RESULTS: Nearly 50% of rectal cancer recurrences are local and are therefore potentially amenable to curative resection. Preoperative imaging is important for appropriate selection of patients for surgery and preoperative adjuvant therapy is essential. Five-year survival following resection ranges from 18% to 58% with 5-year survival following complete resection of over 35% though morbidity ranges from 21% to 82%. Neoadjuvant radiotherapy is beneficial and IORT may have a contributory role in treatment. Aggressive surgical treatment favourably affects quality of life and is cost effective. Surgery for local recurrence can result in significant long-term survival with acceptable morbidity and improved quality of life in appropriately selected patients. Assessment in a specialist centre familiar with these techniques is essential.     

Skin-sparing mastectomy and immediate breast reconstruction: incidence of recurrence in patients with invasive breast cancer

The aim of this study was to investigate whether skin-sparing mastectomy (SSM), which is gaining increasing importance and gives well-accepted cosmetic results, provides adequate treatment of the patients' oncologic disease. From 1995 to 2003, 60 patients diagnosed with invasive breast cancer were treated with SSM and complete axillary dissection. All patients underwent immediate breast reconstruction after primary surgery. Patients were treated either with a latissimus dorsi flap or with a transversus rectus abdominis myocutaneous flap. Depending on the intraoperative analysis of frozen sections, 14 patients were treated with preservation of the nipple-areola complex. During a median follow-up of 52 months (4-92 months), four local recurrences (6.6%) occurred. One patient was also found to have contralateral breast carcinoma. Three patients developed distant metastases, and two patients died of their disease a mean of 18 months after primary therapy. Factors associated with local recurrence were tumor size, poor tumor differentiation, and positive node involvement. SSM followed by immediate breast reconstruction is an alternative to modified radical mastectomy in a subset of patients with invasive breast cancer. The risk of local recurrence is low and is associated with such factors as tumor stage, poor tumor differentiation, and node-positive disease. This procedure does not increase the risk of distant metastases, which is comparable to that after other surgical approaches.