Intraoperative Radiotherapy for Breast Cancer in Elderly Women.

PURPOSE: To evaluate outcomes and postoperative toxicities after intraoperative radiotherapy (IORT) in elderly women. POPULATION: Women older than 65 years, with infiltrating ductal breast cancer ≤3 cm, expressing estrogen receptor (ER+) without Her2 overexpression, and with negative axillary nodes. TREATMENT: Treatment consisted of partial mastectomy with a sentinel lymph node biopsy (SLNB) procedure; in case of positive SLNB, IORT was cancelled. IORT consisted in a total dose of 20 Gy in 1 fraction delivered at the surface of the applicator with the Intrabeam® technique. RESULTS: IORT was planned to be administered to a total of 225 patients but was cancelled for 34 patients during surgery. Thus 191 patients were analyzed; mean age was 76 years, with 57 patients (30%) >80 years. Despite inclusion criteria, 15 had lobular carcinoma and 7 were triple negative. With a median follow-up of 40 months, we observed only 1 local recurrence, located in the skin over the initial tumor. The 5-year local relapse rate was 1.7%. A wound healing delay (>15 days) was observed in 21 patients (11%). Sixty-six patients (35%) had postoperative complications, mainly grade 2, resolving within a few days. Two patients needed surgical drainage for local abscesses. Long-term (>1 year) cosmetic outcome was evaluated in 120 patients and was judged excellent or good in 102 (91%). CONCLUSION: IORT can be safely given to elderly women, with a good local control rate and without major toxicities.

Prognostic Impact of Stromal Immune Infiltration before and after Neoadjuvant Chemotherapy (NAC) in Triple Negative Inflammatory Breast Cancers (TNIBC) Treated with Dose-Dense Dose-Intense NAC.

Inflammatory breast cancers are very aggressive, and among them, triple negative breast cancer (TNBC) has the worst prognosis. While many studies have investigated the association between tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) and outcome in TNBC, the impact of post-NAC TIL and TIL variation in triple negative inflammatory breast cancer (TNIBC) outcome is unknown. Between January 2010 to December 2018, all patients with TNIBC seen at the breast disease unit (Saint-Louis Hospital) were treated with dose-dense dose-intense NAC. The main objective of the study was to determine factors associated with event-free survival (EFS), particularly pathological complete response (pCR), pre- and post-NAC TIL, delta TIL and post-NAC lymphovascular invasion (LVI). After univariate analysis, post-NAC LVI (HR 2.06; CI 1.13-3.74; p = 0.02), high post-NAC TIL (HR 1.81; CI 1.07-3.06; p = 0.03) and positive delta TIL (HR 2.20; CI 1.36-3.52; p = 0.001) were significantly associated with impaired EFS. After multivariate analysis, only a positive TIL variation remained negatively associated with EFS (HR 1.88; CI 1.05-3.35; p = 0.01). TNIBC patients treated with intensive NAC who present TIL enrichment after NAC have a high risk of relapse, which could be used as a prognostic marker in TNIBC and could help to choose adjuvant post-NAC treatment.

10-Year follow-up of 621 patients treated using high-dose rate brachytherapy as ambulatory boost technique in conservative breast cancer treatment.

PURPOSE: Breast conserving treatment, consisting of lumpectomy followed by whole-breast irradiation, is considered the standard of care in early-stage breast cancer. Randomized studies have reported that delivering boost doses to tumor bed improves local control rates, particularly in young women. This study sought to evaluate local control and cosmetic results of delivering boost doses using a high-dose-rate (HDR) brachytherapy (HDRBT) in breast cancer conservative treatment. METHODS: We included 621 T1-T2, N0-N1 breast cancer patients who underwent lumpectomy, external irradiation (44Gy over 5weeks), and a boost dose of two fractions of 5Gy to the tumor bed by means of HDR iridium brachytherapy. Implantation was performed during the lumpectomy or 2-3weeks after external irradiation. Population characteristics were as follows: pTis=11.6%; pT1=63.4%; pT2=25.0%; median tumor size=1.5cm; histology: ductal carcinoma in situ (DCIS): 72 (11.6%); infiltrative ductal carcinoma (IDC): 471 (75.8%); other: 78 (12.6%). For IDCs, the surgical margins were positive in 38cases (6.2%) and an extensive intraductal component was present in 254 cases. RESULTS: With a median follow-up of 10.3years, 47 local relapses were observed (10-year local relapse rate: 7.4%). Small-volume implantation (V100<45cc) and ductal carcinoma in situ histology both significantly correlated with local relapse. The 10-year overall survival was 91%. Cosmetic results were evaluated in 264patients, proving excellent in 58 (22%), good in 153 (58%), fair in 40 (15%), and poor in 13 (5%). CONCLUSIONS: Small implant volume and ductal carcinoma in situ histology significantly correlated with local relapse following HDR brachytherapy dose boost in breast cancer conservative treatment. Modern image-guided breast brachytherapy techniques using surgical clips as a guide may decrease potential treatment targeting errors, consequently improving local control without increasing toxicity.

p53 in breast cancer subtypes and new insights into response to chemotherapy.

Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer. Recent findings may lead to reconsider the role of p53 in breast cancer. TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Their distribution is highly linked to molecular tumor subtypes found in 26% of luminal tumors (17% of luminal A, 41% of luminal B), in 50% of HER2 amplified tumors, in 69% of molecular apocrine breast carcinomas and in 88% of basal-like carcinomas. The type of mutation is linked to the tumor subtype with higher frequency of base-pair substitutions in luminal tumors, whereas molecular apocrine and basal-like tumors present much higher frequency of complex mutations (deletions/insertions). The timing of TP53 mutation also depends on the tumor subtype, being the first important event in luminal tumors but occurring after PTEN loss in basal-like tumors. Regarding response to cytotoxic chemotherapy, the situation is far from the p53-dependent apoptosis paradigm with subsequent clinical response. We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin-cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response. Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells. A recent work confirmed these findings in MMTV-Wnt1 mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response. Furthermore, in ER positive (ER(+)) breast tumors, it has been recently reported that ER represses the p53-mediated apoptotic response induced by DNA damage. Taken together, these data can help to better understand p53-mediated response to doxorubicin-based chemotherapy in breast cancer: in ER(+) TP53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment. Conversely, in ER negative (ER(-)) TP53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response. In view of these recent results, p53 impact in breast cancer should be reconsidered.

Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15.

INTRODUCTION: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. RESULTS: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. CONCLUSION: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.

[Neoadjuvant treatment of early breast cancer: new drugs contribution]. / Traitement néoadjuvant du cancer du sein: place des nouvelles drogues.

Neodjuvant chemotherapy has been primitively used in locally advanced breast cancer. More recently, indications have been extended to operable lesions. Several randomized trials have compared preoperative chemotherapy with postoperative surgery. None of these studies with anthracyclines have shown benefit in terms of progression free survival and/or overall survival. The rate of breast-conservative surgery seems slightly increased. However, in the NSABP 18 study, there was also a marginally significant increase in local recurrence when patients were converted from mastectomy lumpectomy to as originally planned. The introduction of taxanes in neoadjuvant chemotherapy protocol leads to a better clinical response and a complete histological responses increase when docetaxel is used. In only one study using docetaxel after anthracyclin treatment, a survival benefit is reported but it is a small study; a longer follow up and the updated results of the NSABP B27 trial are needed to confirm the impact of taxotere in the outcome of breast cancer. The integration of trastuzumab with taxane based chemotherapy has already shown high rate of histological complete responses. At least, neoadjuvant chemotherapy has the advantage to study biologic predictive factors of chemotherapy response. This article will review data on standard therapeutic and new agents in neoadjuvant treatment.

Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes.

PURPOSE: To determine the incidence and prognostic significance of eradication of cytologically proven axillary lymph node metastases in breast cancer patients treated with primary chemotherapy. PATIENTS AND METHODS: Between January 1985 and December 1994, 152 breast cancer patients with invasive T1 to T3 tumors and axillary metastases cytologically proven by fine-needle sampling underwent primary chemotherapy followed by lumpectomy or mastectomy, level I and II axillary lymph node dissection, and irradiation. We studied pathologic complete responses (pCRs) of axillary nodes and breast tumors, as well as predictors of distant metastases. RESULTS: Thirty-five patients (23%) had axillary pCRs, and 20 patients (13.2%) had pCRs of primary breast tumors. Scarff-Bloom-Richardson grade 3 tumors (P =.04) and a clinical response to chemotherapy > or = 50% (P =.003) were associated with negative axillary status at dissection. An initial tumor size < or = 3 cm (63 patients) was associated with pCR of the primary tumor (P =.02) but not with complete histologic clearance of axillary lymph nodes. The median length of follow-up was 75 months. In the univariate analysis, age greater than 40 years (P =.003), absence of residual nodal disease (P =.01), and pCR of the tumor (P =.05) were associated with better distant disease-free survival. Five-year distant disease-free survival rates were 73.5% +/- 14.9% among patients with no involved nodes at the time of surgery and 48.7% +/- 9.2% among patients with residual nodal disease. In the multivariate Cox regression analysis, parameters associated with poor distant disease-free survival were age < or = 40 years (P =.002), persistence of nodal involvement (P =.03), and S-phase fraction greater than 4% (P =.02). CONCLUSION: Our results suggest that axillary status is a better prognostic factor than response of the primary tumor to primary chemotherapy.