Rassegna della letteratura – febbraio 2019

Trattamento loco-regionale: chirurgia oncologica, plastica e radioterapia

Zarba Meli E, Cattin F, Curcio A et Al – Surgical delay may extend the indications for nipple-sparing mastectomy: A multicentric study. – Eur J Surg Oncol. 2019 Feb 14. pii: S0748-7983(19)30284-7.

Purpose: nipple-sparing mastectomy (NSM) is considered an oncologically sound procedure but necrosis of the nipple-areola complex (NAC) or skin flaps is a concern, particularly in the presence of risk factors. To increase the indications for NSM and decrease such complications, different procedures of “surgical delay” (SD) have been described.

Methods: a retrospective analysis of patients who underwent SD for NSM at four Italian Breast Centers from 2014 to 2017 was performed. SD generally consisted of a periareolar or “hemi-batwing” incision, dissecting the skin and the NAC from the underlying breast tissue. NSM was scheduled after 2-3 weeks.

Results: Eeghty-eight procedures were analyzed. Mild complications of SD were registered in 7.9% of cases. NSM was performed in 85 cases, whereas in three cases (3.4%) a “skin-sparing” mastectomy was necessary due to positivity of the retroareolar biopsy for cancer at SD. A direct-to- implant (DTI) reconstruction was performed in 42 cases (49.4%), while in 43 (50.6%) a tissue-expander (TE) was inserted. After NSM, eight complications (9.4%) were recorded: one total necrosis (1.2%), one partial necrosis (1.2%) and four minimal ischemia (4.7%) of NAC, one skin flap necrosis (1.2%), one haematoma (1.2%). In only two cases (2.3%) prosthesis removal was needed. Aesthetic outcome was evaluated excellent or good in 92.9% of cases. At a median follow-up of 24 months no local recurrences were seen.

Conclusions: this is the largest series of SD with NSM presented so far in the literature. In our experience, SD extends indications for NSM in high-risk women.

Marta GN, Barrett J, Porfirio GJM et Al. – Effectiveness of different accelerated partial breast irradiation techniques for the treatment of breast cancer patients: Systematic review using indirect comparisons of randomized clinical trials. – Rep Pract Oncol Radiother. 2019 Mar-Apr;24(2):165-174.

Purpose This systematic review was conducted to compare the effectiveness of different accelerated partial breast irradiation (APBI) techniques for the treatment of breast cancer patients.

Methods Systematic review of randomized controlled trials of APBI versus whole breast irradiation (WBI). The data from APBI studies were extracted for the analyses. Indirect comparisons were used to compare different APBI techniques

Results Ten studies fulfilled the inclusion criteria. A total of 4343 patients were included, most of them with tumor stage T1-T2 and N0. Regarding APBI techniques, six trials used external beam radiation therapy; one intraoperative electrons; one intraoperative low-energy photons; one brachytherapy; and one external beam radiation therapy or brachytherapy. The indirect comparisons related to 5-years local control and 5-years overall survival were not significantly different between APBI techniques.

Conclusions Based on indirect comparisons, no differences in clinical outcomes were observed among diverse APBI techniques in published clinical trials that formally compared WBI to APBI. However wide confidence intervals and high risk of inconsistency precluded a sound conclusion. Further head-to-head clinical trials comparing different APBI techniques are required to confirm our findings. Studies comparing different techniques using individual participant data and/or real-life data from population-based studies/registries could also provide more robust results.

Vallard A, Magné N, Guy JB et Al. – Is breast-conserving therapy adequate in BRCA 1/2 mutation carriers? The radiation oncologist’s point of view – Br J Radiol. 2019 Feb 27:20170657.

Breast conserving therapy (BCT) is currently a recognized alternative to mastectomy for early BC patients. However, the therapeutic index of BCT was considered controversial for decades in BRCA1/2 mutation carriers. The aim of the present review was to investigate the outcome of mutation carriers undergoing BCT regarding local and distant endpoints. A short review was performed from the point of view of the radiation oncologist. Only retrospective data were available regarding local outcome assessment. They generated conflicting results. In studies with limited follow-up, BCT did not increase the risk of local recurrence in BRCA1/2 mutation carriers versus non-carriers. Conversely, some studies with longer follow-up supported that local relapse was increased in mutation carriers. Yet, according to some publications, their long-term risk of ipsilateral recurrence post-BCT was not different from general population cohorts. Besides, overall and metastasis-free survivals were the same after BCT regardless of the BRCA1/2 mutation status. Similar survival rates were also reported when BCT and mastectomy were compared in mutation carriers. Regarding acute or late toxicity, normal rates were reported in BRCA mutation carriers after breast radiotherapy. The BRCA1/2 mutation does not seem to widely alter the therapeutic index (efficacy/toxicity ratio) of modern adjuvant breast irradiation. Although the long term equivalence of BCT/mastectomy on local control is still not clearly recognised, BCT can be considered an adequate option for BRCA1/2 mutation carriers. This review highlights that BCT is a reasonable option for BRCA1/2 mutation carriers however litterature is controversial concerning long-term local outcome and results of a large prospective cohort are needed.

Magnoni F, Massari G, Santomauro G et Al – Sentinel lymph node biopsy in microinvasive ductal carcinoma in situ. – Br J Surg. 2019 Mar;106(4):375-383. doi: 10.1002/bjs.11079. Epub 2019 Feb 21.

Purpose/background Microinvasive breast cancer is an uncommon pathological entity. Owing to the rarity of this condition, its surgical axillary management and overall prognosis remain controversial.

Methods A database was analysed to identify patients with microinvasive ductal carcinoma in situ (DCIS) who had surgery for invasive breast cancer at the European Institute of Oncology, Milan, between 1998 and 2010. Women who had undergone axillary staging by sentinel lymph node biopsy were included in the study.

Results Of 257 women with microinvasive breast cancer who underwent sentinel lymph node biopsy (SLNB), 226 (87·9 per cent) had negative sentinel lymph nodes (SLNs) and 31 had metastatic SLNs. Twelve patients had isolated tumour cells (ITCs), 14 had micrometastases and five had macrometastases in sentinel nodes. Axillary lymph node dissection was performed in 16 of the 31 patients with positive SLNs. After a median follow-up of 11 years, only one regional first event was observed in the 15 patients with positive SLNs who did not undergo axillary lymph node dissection. There were no regional first events in the 16 patients with positive SLNs who had axillary dissection.

Conclusions Good disease-free and overall survival were found in women with positive SLNs and microinvasive DCIS. This study is in line with studies showing that SLNB in microinvasive DCIS may not be useful, and supports the evidence that less surgery can provide the same level of overall survival with better quality of life.

Mirzabeigi MN, Rhemtulla IA et Al – Locoregional cancer recurrence after breast reconstruction: detection, management, and secondary reconstructive strategies – Plast Reconstr Surg. 2019 Feb 13.

Purpose/backgroundLocoregional recurrence (LRR) of the previously reconstructed breast poses a diagnostic and operative challenge. This study examines detection, management, and reconstructive strategies of LRR following post-mastectomy breast reconstruction

Methods A retrospective review of records was performed on patients treated within the health system for breast cancer from January 2000 – July 2014. Of these patients, descriptive factors and operative details were collected for those that developed LRR. Subsequent reconstructive surgeries were also examined. Utilizing a multidisciplinary team, a surveillance/management algorithm was generated.

Results A total of 41 patients with LRR were identified (mean time to recurrence 4.6 years). 2-year and 5-year survival following LRR was 88 percent and 39 percent respectively. LRR was found to occur in the following tissue planes: subcutaneous (27 percent), subcutaneous/pectoralis (24 percent), chest wall (37 percent), and axillary (12 percent). The most frequent method of detection was patient concern leading to examination. Older age at the time of LRR (p=0.028), increased time to recurrence /detection (p=0.024), and chemotherapy before LRR (p=0.014) were associated with the need for a secondary salvage flap. Patients who experienced a subcutaneous recurrence were far less likely to undergo a secondary flap (p=0.011). Factors associated with loss of the index reconstruction included lower BMI (p=0.009), pectoralis invasion (p=0.05), and implant reconstruction (p=0.03).

Conclusions Detection and management of LRR requires appropriate physical exam and imaging. Significant factors associated with failure to salvage the initial reconstruction included BMI, plane of recurrence and type of initial reconstruction.

Pommier SJ, Morgan RE, Limbach KE et Al. – Surgical resection of breast cancers: Molecular analysis of cancer stem cells in residual disease – Surgery. 2019 Feb 15.

Purpose/background Approximately 70% of breast cancer patients have residual disease after neoadjuvant chemotherapy. This study was designed to determine whether breast cancer cells with stemlike properties are present in residual disease after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The presence of breast cancer cells with stemlike properties with specific mutations may help explain the poor prognosis associated with residual disease.

Methods A total of 68 breast cancer specimens were collected at the time of mastectomy or lumpectomy. A total of 44 were chemotherapy naïve and 24 were collected as residual disease after neoadjuvant chemotherapy. Tumor cells were collected by fluorescence-activated cell sorting, with breast cancer cells with stemlike properties specifically identified using breast stem cell associated antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast cancer cells with stemlike properties were analyzed for genetic mutations, including PIK3CA.

Results Breast cancer cells with stemlike properties, demonstrating EpCAM-positive, CD44-positive, CD49f±, CD24± expression were present in chemotherapy-naïve tumors and residual disease. In both chemotherapy-naïve and residual disease specimens the highest frequency of PIK3CA mutations were detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were detected in all stages of breast cancer (35%), in both chemotherapy naïve (39%) and residual disease (29%) and in both estrogen receptor positive (41%) and negative tumors (14%) (P = ns). Various PIK3CA mutations were identified in chemotherapy-naïve specimens versus residual disease specimens in both patient-paired and unpaired breast cancers.

Conclusions Breast cancer cells with stemlike properties with mutations in PIK3CA were present in chemotherapy-naïve breast cancers and residual disease after neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy does not completely eradicate PIK3CA-defective breast cancer cells with stemlike properties. Although these findings may help explain the poor clinical outcomes in patients with residual disease, they also identify breast cancer cells with stemlike-property targets for therapies.

Bateni SB, Davidson AJ et Al. – Is Breast-Conserving Therapy Appropriate for Male Breast Cancer Patients? A National CancerDatabase Analysis – Ann Surg Oncol. 2019 Feb 13.

Purpose/background Current treatment guidelines for male breast cancer are predominantly guided by female-only clinical trials. With scarce research, it is unclear whether breast-conserving therapy (BCT) is equivalent to mastectomy in men. We sought to compare overall survival (OS) among male breast cancer patients who underwent BCT versus mastectomy.

Methods We performed a retrospective analysis of 8445 stage I-II (T1-2 N0-1 M0) male breast cancer patients from the National CancerDatabase (2004-2014). Patients were grouped according to surgical and radiation therapy (RT). BCT was defined as partial mastectomy followed by RT. Multivariable and inverse probability of treatment-weighted (IPTW) Cox proportional hazards models were used to compare OS between treatment groups, controlling for demographic and clinicopathologic characteristics.

Results Most patients underwent total mastectomy (61.2%), whereas 18.2% underwent BCT, 12.4% underwent total mastectomy with RT, and 8.2% underwent partial mastectomy alone. In multivariable and IPTW models, partial mastectomy alone, total mastectomy alone, and total mastectomy with RT were associated with worse OS compared with BCT (p < 0.001 all). Ten-year OS was 73.8% for BCT and 56.3, 58.0 and 56.3% for other treatment approaches. Older age, higher T/N stage, histological grade, and triple-negative receptor status were associated with poorer OS (p < 0.05). Subgroup analysis by stage demonstrated similar results.

Conclusions In this national sample of male breast cancer patients, BCT was associated with greater survival. The underlying mechanisms of this association warrant further study, because more routine adoption of BCT in male breast cancer appears to translate into clinically meaningful improvements in survival.