How Often Does Modern Neoadjuvant Chemotherapy Downstage Patients to Breast-Conserving Surgery?

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been proven to increase breast-conserving surgery (BCS) rates, but data are limited on conversion rates from BCS-ineligible (BCSi) to BCS-eligible (BCSe), specifically, in patients with large tumors. METHODS: Consecutive patients with stage I-III breast cancer treated with NAC from November 2013 to March 2019 were identified. BCS eligibility before and after NAC was prospectively determined. Patients deemed BCSi before NAC due to large tumor size were studied. Statistical analyses were conducted using Student's t-test, Wilcoxon rank sum test, Chi-square test, Fisher's test, and logistic regression. RESULTS: In this study, 600 of 1353 cancers were BCSi with large tumors; 69% were non-BCS candidates, 31% were borderline-BCS (bBCS) candidates. Of non-BCS candidates, 69% became BCSe after NAC; 66% chose BCS, and 90% were successful. Among bBCS candidates, 87% were BCSe after NAC, 73% chose BCS, and 96% were successful. On univariate analysis, bBCS candidacy, lower cT stage, cN0 status, absence of calcifications, human epidermal growth factor receptor 2 positive (HER2+)/triple negative (TN) receptor status, poor differentiation, ductal histology, and breast pCR were associated with conversion to BCS eligibility. On multivariable analysis, receptor status (hormone receptor positive [HR+]/HER2- ref; odds ratio [OR] HER2+ 1.63, P = 0.047; HR-/HER2- OR, 2.26, P = 0.003) and breast pCR (OR 2.62, P < 0.001) predicted successful downstaging, while larger clinical tumor size (OR 0.86, P = 0.003), non-BCS candidacy (OR 0.46, P = 0.003), cN+ status (OR 0.54, P = 0.008), and calcifications (OR 0.56, P = 0.007) predicted lower downstaging rates. CONCLUSION: In patients with large tumors precluding BCS, conversion to BCS eligibility was high with NAC, particularly in bBCS candidates. HER2+/TN receptor status predicted successful downstaging, while lower downstaging rates were observed with larger tumors, cN+ status, and calcifications. These factors should be considered when selecting patients for NAC.

Differences between screen-detected and interval breast cancers among BRCA mutation carriers.

BACKGROUND: BRCA mutation carriers have an elevated lifetime breast cancer risk and remain at risk for interval cancer development. We sought to compare BRCA mutation carriers with screen-detected versus interval breast cancers. METHODS: Women with a known BRCA mutation prior to a breast cancer diagnosis were identified. Clinical and pathologic factors, and imaging within 18 months of diagnosis were compared among screen-detected versus interval cancers. Interval cancers were those detected by physical exam among women undergoing regular screening. RESULTS: Of 124 breast cancers, 92 were screen and 22 clinically detected, of which 11 were interval cancers among regular screeners, and 10 were incidentally found on prophylactic mastectomy. Women with interval cancers were younger, had lower body mass indexes, and were more likely to be Black than those with screen-detected cancers (p < 0.05). Interval cancers were all invasive, larger, more likely to be node positive, and more likely to require axillary lymph node dissection and chemotherapy (p < 0.05). No significant differences were seen by BRCA mutation, mammographic density, MRI background parenchymal enhancement, tumor grade, or receptor status between cohorts. Women screened with both mammogram and MRI had significantly lower proportions of interval cancers compared to women screened with only mammogram or MRI alone (p < 0.05). CONCLUSIONS: Interval breast cancers among BRCA mutation carriers have worse clinicopathologic features than screen-detected tumors, and require more-aggressive medical and surgical therapy. Imaging with mammogram and MRI is associated with lower interval cancer development and should be utilized among this high-risk population.

Does nonmetastatic inflammatory breast cancer have a worse prognosis than other nonmetastatic T4 cancers?

BACKGROUND: Both patients with inflammatory breast cancer (IFLBC) and patients with noninflammatory T4 breast cancer (non-IFLBC) have a heavy disease burden in the breast; whether the unique biology of IFLBC conveys a higher locoregional recurrence (LRR) risk and worse outcomes in comparison with other T4 lesions is uncertain. Here the outcomes of patients with IFLBC and patients with non-IFLBC treated with modern multimodality therapy are compared. METHODS: Patients with nonmetastatic T4 breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiation therapy between 2006 and 2016 were identified. Recurrences and survival were compared between patients with IFLBC and patients with non-IFLBC overall and stratified by receptor subtype. RESULTS: For 199 T4 patients, the median age was 52 years, and the median clinical tumor size was 7 cm. One hundred seventeen (59%) had IFLBC. With a median follow-up of 41 months, 4 patients had isolated LRR; all cases occurred in patients with IFLBC. The 5-year isolated LRR rate for patients with IFLBC was 4.8%. Overall, 14 patients had both LRR and distant recurrence (DR); 47 had DR only. The 5-year distant recurrence-free survival (DRFS) rates were similar for patients with IFLBC and patients with non-IFLBC (63% vs 71%; log-rank P = .14). The 5-year DRFS rate was lowest among triple-negative (TN) patients (43%) and was significantly lower for patients with TN IFLBC versus patients with non-IFLBC (28% vs 62%; log-rank P = .02). The 5-year overall survival rates (71% vs 74%; log-rank P = .4) and cancer-specific survival rates (74% vs 79%; log-rank P = .23) did not differ between IFLBC and non-IFLBC. CONCLUSIONS: Although IFLBC is often considered a unique biologic subtype, patients with IFLBC and patients with non-IFLBC had similar outcomes with modern multimodality therapy; isolated LRR was uncommon. The TN subtype in patients with IFLBC is associated with poor outcomes, and this indicates the need for new treatment approaches in this group.

Axillary Dissection and Nodal Irradiation Can Be Avoided for Most Node-positive Z0011-eligible Breast Cancers: A Prospective Validation Study of 793 Patients.

OBJECTIVE: To determine rates of axillary dissection (ALND) and nodal recurrence in patients eligible for ACOSOG Z0011. BACKGROUND: Z0011 demonstrated that patients with cT1-2N0 breast cancers and 1 to 2 involved sentinel lymph nodes (SLNs) having breast-conserving therapy had no difference in locoregional recurrence or survival after SLN biopsy alone or ALND. The generalizability of the results and importance of nodal radiotherapy (RT) is unclear. METHODS: Patients eligible for Z0011 had SLN biopsy alone. Prospectively defined indications for ALND were metastases in ≥3 SLNs or gross extracapsular extension. Axillary imaging was not routine. SLN and ALND groups and radiation fields were compared with chi-square and t tests. Cumulative incidence of recurrences was estimated with competing risk analysis. RESULTS: From August 2010 to December 2016, 793 patients met Z0011 eligibility criteria and had SLN metastases. Among them, 130 (16%) had ALND; ALND did not vary based on age, estrogen receptor, progesterone receptor, or HER2 status. Five-year event-free survival after SLN alone was 93% with no isolated axillary recurrences. Cumulative 5-year rates of breast + nodal and nodal + distant recurrence were each 0.7%. In 484 SLN-only patients with known RT fields (103 prone, 280 supine tangent, 101 breast + nodes) and follow-up ≥12 months, the 5-year cumulative nodal recurrence rate was 1% and did not differ significantly by RT fields. CONCLUSIONS: We confirm that even without preoperative axillary imaging or routine use of nodal RT, ALND can be avoided in a large majority of Z0011-eligible patients with excellent regional control. This approach has the potential to spare substantial numbers of women the morbidity of ALND.

Standard Pathologic Features Can Be Used to Identify a Subset of Estrogen Receptor-Positive, HER2 Negative Patients Likely to Benefit from Neoadjuvant Chemotherapy.

BACKGROUND: The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR). OBJECTIVE: The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC. METHODS: Patients with stage I-III ER+, HER2- breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP). RESULTS: From 2007 to 2016, 402 ER+/HER2- cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II-III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p < 0.0001). Patients with ILC initially ineligible for BCS (n = 56) were less likely to downstage than those with invasive ductal carcinoma (IDC; n = 183, 16 vs. 48%, p ≤ 0.0001), with a similar trend in the axilla (p = 0.086). The rates of BCS eligibility after NAC were highest in PR-/HP patients (62%) and lowest in PR+/non-HP patients (29%) [p = 0.005]. In the axilla, nodal pCR among cN+ patients (n = 301) ranged from 0 to 35% (p < 0.0001) within these groups, and was most frequent in PR-/HP patients. CONCLUSIONS: ER+/HER2- patients most likely to benefit from NAC are those with PR- and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach.

Is Unilateral Implant or Autologous Breast Reconstruction Better in Obtaining Breast Symmetry?

Unilateral breast reconstruction poses a special set of challenges to the reconstructive breast surgeon compared to bilateral reconstructions. No studies to date provide an objective comparison between autologous and implant based reconstructions in matching the contralateral breast. This study compares the quantitative postoperative results between unilateral implant and autologous flap reconstructions in matching the native breast in shape, size, and projection using three-dimensional (3D) imaging. Sixty-four patients who underwent unilateral mastectomy with tissue expander (TE)-implant (n = 34) or autologous microvascular free transverse rectus abdominus myocutaneous (TRAM; n = 18) or deep inferior epigastric artery perforator (DIEP; n = 12) flap (n = 30) reconstruction from 2007 to 2010 were analyzed. Key patient demographics and risk factors were collected. Using 3D scans of patients obtained during pre and postoperative visits including over 1 year follow-ups for both groups, 3D models were constructed and analyzed for total breast volume, anterior-posterior projection from the chest wall, and 3D comparison. No significant differences in mean age, body mass index, or total number of reconstructive surgeries were observed between the two groups (TE-implant: 52.2 ± 10, 23.9 ± 3.7, 3 ± 0.9; autologous: 50.7 ± 9.4, 25.4 ± 3.9, 2.9 ± 1.3; p > 0.05). The total volume difference between the reconstructed and contralateral breasts in the TE-implant group was insignificant: 27.1 ± 22.2 cc, similar to the autologous group: 29.5 ± 24.7 cc, as was the variance of breast volume from the mean. In both groups, the reconstructed breast had a larger volume. A-P projections were similar between the contralateral and the reconstructed breasts in the TE-implant group: 72.5 ± 3.21 mm versus 71.7 ± 3.5 mm (p > 0.05). The autologous reconstructed breast had statistically insignificant but less A-P projection compared to the contralateral breast (81.9 ± 16.1 mm versus 61.5 ± 9.5 mm; p > 0.05). Variance of A-P projection from the mean was additionally insignificant between the contralateral and reconstructed breasts. Both groups produced similar asymmetry scores based on global 3D comparison (TE-implant: 2.24 ± 0.3 mm; autologous: 1.96 ± 0.2 mm; p > 0.05). Lastly, when the autologous group was further subdivided into TRAM and DIEP cohorts, no significant differences in breast volume, A-P projection or symmetry existed. Using 3D imaging, we demonstrate that both TE-implant and autologous reconstruction can achieve symmetrical surgical results with the same number of operations. This study demonstrates that breast symmetry, while an important consideration in the breast reconstruction algorithm, should not be the sole consideration in a patient' decision to proceed with autologous versus TE-implant reconstruction.

Is there an ideal donor site of fat for secondary breast reconstruction?

BACKGROUND: Loss of volume after autologous fat transfer to the breast is well documented, and various methods to improve long-term survival of fat grafts have been investigated (including both distant and neighboring harvest sites), but no optimal technique has been identified. OBJECTIVE: The authors compare fat graft survival from 2 anatomical donor sites to determine whether there is an optimal site for fat graft harvesting in breast reconstruction. METHODS: Seventy-three patients (109 breasts) who received fat grafting to reconstructed breasts from 2009 to 2012 were enrolled in this retrospective study and divided into 2 groups: group A had fat harvested from the abdomen and group B from the thighs. Fat grafting was performed using a modified Coleman technique for symmetry. For all patients, 3-dimensional scans were obtained and volumes were analyzed. RESULTS: Forty-six patients (66 breasts) received an average of 101 mL of fat injected from the abdomen, and 27 (43 breasts) received an average of 102 mL from the thighs. Group A had 82% volume retention at 16 days, 63% at 49 days, and 45% at 140 days. Group B had 86% at 16 days, 63% at 49 days, and 46% at 140 days (P > .05). Patients were also stratified by radiation exposure and volume injected; neither affected donor site volume retention (P > .05). CONCLUSIONS: Our data suggest that donor site, regardless of volume injected or tissue radiation, did not affect volume retention in fat grafting. Longer-term studies are needed to assess the stability of the breast after fat grafting.

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

Analysis of protocadherin alpha gene deletion variant in bipolar disorder and schizophrenia.

OBJECTIVES: The cell adhesion proteins protocadherins and cadherins, through their effects on guiding neurons during development, neuronal differentiation, and synaptogenesis, are feasible targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Thus, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider as underlying susceptibility factors. One such set of candidate genes is the 5q31-linked PCDH family. A polymorphic copy number variation in this locus, a 16.7-kb deletion affecting PCDH-alpha exons 8-10 (alpha 8-alpha 10 Delta), was analyzed in this study as a potential candidate variant in SZ and BD. METHODS: The frequency of the alpha 8-alpha 10 Delta variant was determined in a cohort of Caucasian patients with SZ from the United States and a cohort of patients with BD from the Czech Republic, and corresponding controls by amplifying DNA with deletion specific primers followed by gel electrophoresis. RESULTS: No significant difference was observed in the frequency of the alpha 8-alpha 10 Delta variant in patients with SZ or BD compared with their respective controls. CONCLUSION: Although the results of this study were negative, theoretical considerations and linkage studies suggest that the 5q31-linked PCDH family should be analyzed as a potential locus underlying SZ and BD susceptibility.

Increase in GSK3beta gene copy number variation in bipolar disorder.

The analysis of submicroscopic copy number variations (CNVs), also known as copy number polymorphisms (CNPs), is emerging as a new tool for understanding the genetic basis of cancer, developmental disorders, and complex traits. One area where this may be particularly useful is in the identification of genetic variants underlying schizophrenia (SZ) and bipolar disorder (BD). Linkage analysis and pharmacological studies carried out over the past decade have implicated a number of positional and physiological candidate genes. Yet, despite extensive analysis, the underlying allelic variants responsible for disease susceptibility have remained, largely, elusive. Although the borders of most CNV have not been precisely mapped, it appears that a considerable number of SZ and BD candidate genes have their coding elements disrupted by polymorphic CNVs, suggesting that these would be good variants to consider for underlying disease susceptibility. One such gene is GSK3beta, which codes for glycogen synthase kinase, a key component of the Wnt signaling pathway and a target of lithium salts. A CNV in the GSK3beta locus at chromosome 3q13.3 appears to disrupt the gene's 3'-coding elements. The CNV also affects two other annotated genes. We now report that patients with BD have an increased frequency of this CNV-primarily the duplication variant-compared with controls (P = 0.002). The finding suggests that GSK3beta may be involved in BD susceptibility in some individuals and that CNVs in this and other candidate genes for psychiatric disorders should be analyzed as causative functional genetic variants.