Phase 2 study of pre-excision single-dose intraoperative radiation therapy for early-stage breast cancers: six-year update with application of the ASTRO accelerated partial breast irradiation consensus statement criteria.

BACKGROUND: Intraoperative radiation therapy (IORT) allows delivery of high-dose radiation at the time of lumpectomy, potentially sparing adjuvant daily radiation. A phase 2 study of pre-excision IORT was performed for early-stage breast cancer. METHODS: Patients ≥ 48 years of age with invasive ductal carcinoma, ≤ 3 cm, and clinically node-negative were eligible for this study, which was approved by institutional review board. Ultrasound was used to select electron energy and cone size to cover the tumor plus 1.5- to 2.0-cm lateral margins and 1-cm-deep margins (90% isodose). Fifteen Gy was delivered with a Mobetron irradiator, and immediate needle-localized partial mastectomy followed. Local event results were updated using the Kaplan-Meier method. RESULTS: A total of 53 patients received IORT alone. Median age was 63 years, and median tumor size was 1.2 cm. Of these, 81% were positive for estrogen receptor or progesterone receptor, 11% were positive for human epidermal growth factor receptor 2, and 15% were triple-negative. Also, 42%, 49%, and 9% would have fallen into the Suitable, Cautionary, and Unsuitable groups, respectively, of the American Society of Therapeutic Radiation Oncology consensus statement for accelerated partial breast irradiation. Median follow-up was 69 months. Ipsilateral events occurred in 8 of 53 patients. The 6-year actuarial rate of ipsilateral events was 15% (95% confidence interval = 7%-29%). The crude event rate for Suitable and Cautionary groups was 1 of 22 (5%) and 7 of 26 (27%), respectively. Overall survival was 94.4%, and breast cancer-specific survival was 100%. CONCLUSIONS: The rate of local events in this study is a matter of concern, especially in the Cautionary group. On the basis of these findings, pre-excision IORT, as delivered in this study, may not provide adequate local control for less favorable early-stage breast cancers.

Phase I study and biomarker analysis of lapatinib and concurrent radiation for locally advanced breast cancer.

PURPOSE: This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways. METHODS: Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry. RESULTS: Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation. CONCLUSIONS: The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.

Cosmetic outcomes for accelerated partial breast irradiation before surgical excision of early-stage breast cancer using single-dose intraoperative radiotherapy.

PURPOSE: Determine cosmetic outcome and toxicity profile of intraoperative radiation delivered before tumor excision for patients with early-stage breast cancer. METHODS AND MATERIALS: Patients age 48 or older with ultrasound-visible invasive ductal cancers <3 cm and clinically negative lymph nodes were eligible for treatment on this institutional review board-approved Phase II clinical trial. Treatment planning ultrasound was used to select an electron energy and cone size sufficient to cover the tumor plus a 1.5- to 2.0-cm circumferential margin laterally and a 1-cm-deep margin with the 90% isodose line. The dose was prescribed to a nominal 15 Gy and delivered using a Mobetron electron irradiator before tumor excision by segmental mastectomy. Physician- and patient-assessed cosmetic outcome and patient satisfaction were determined by questionnaire. RESULTS: From March 2003 to July 2007, 71 patients were treated with intraoperative radiation therapy. Of those, 56 patients were evaluable, with a median follow-up of 3.1 years (minimum 1 year). Physician and patient assessment of cosmesis was "good or excellent" (Radiation Therapy Oncology Group cosmesis scale) in 45/56 (80%) and 32/42 (76%) of all patients, respectively. Eleven patients who received additional whole breast radiation had similar rates of good or excellent cosmesis: 40/48 (83%) and 29/36 (81%), respectively). Grade 1 or 2 acute toxicities were seen in 4/71 (6%) patients. No Grade 3 or 4 toxicities or serious adverse events have been seen. CONCLUSION: Intraoperative radiotherapy delivered to an in situ tumor is feasible with acceptable acute tolerance. Patient and physician assessment of the cosmetic outcome is good to excellent.

Local control following single-dose intraoperative radiotherapy prior to surgical excision of early-stage breast cancer.

BACKGROUND: Multiple partial breast radiotherapy techniques are available. We have previously presented the technical details of our procedure of delivering partial breast irradiation with a single fraction of intraoperative radiotherapy (IORT) targeting the tumor in situ prior to partial mastectomy. This study details our completed, single-institution trial. MATERIALS AND METHODS: An IRB-approved, DSMB-monitored phase II trial was performed with the following inclusion criteria: women age ≥48, ultrasound-visible invasive ductal cancers <3 cm, clinically negative axillary nodes. IORT was delivered using mobile electron irradiator, at least a 1.5-cm radial and 1-cm deep margin; patients received 15 Gy and immediately underwent partial mastectomy. Ipsilateral breast recurrence was classified as true/marginal, elsewhere in the breast or nodal basin. Kaplan-Meier methods were used to estimate survival functions and exact 95% confidence intervals are reported. RESULTS: Between 2003 and 2007, 71 women underwent IORT (median follow-up: 3.5 years). For patients with tumor-involved or close margins, additional therapy was required: 7 patients, total mastectomy; 11, whole breast radiation. Four women experienced invasive ipsilateral breast failures (1 new primary, 3 margin recurrences) for a 3-year local control rate of 49 of 53 (94.8%; 95% confidence interval 92.4% [95% CI] 84.2­98.3%), actuarial three-year in breast recurrence was 8% (95% CI 2­18%), and breast cancer-specific survival was 100%. CONCLUSIONS: Intraoperative radiotherapy delivered to an in situ tumor is feasible, but our local control rate at 3.5 years is concerning. Possible changes to this technique to improve local control rates include better preoperative imaging (MRI), routine intraoperative ultrasound, and improved IORT delivery (larger cone, increased dose).

Lapatinib in combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ breast tumor xenografts.

PURPOSE: To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts. METHODS AND MATERIALS: Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry. RESULTS: Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period. In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model. CONCLUSION: Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and that inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively.

Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status.

PURPOSE: Epidermal growth factor receptor (EGFR) family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations. EXPERIMENTAL DESIGN: Expression of EGFR family members in pancreatic cancer lines was assessed by quantitative reverse transcription-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity. RESULTS: Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras-expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was seen in lines expressing mutant K-ras. Overexpression of constitutively active K-ras (G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MAP/ERK kinase/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio, 1.2-1.8) or nelfinavir (enhancement ratio, 1.2-1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras-containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5). CONCLUSIONS: Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other phosphoinositide 3-kinase/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status.

Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: a phase II trial.

PURPOSE: Trastuzumab (Herceptin), an anti-human epidermal growth factor receptor 2 (HER2) antibody, has been shown to be an effective radiosensitizer in preclinical studies. The present Phase II trial evaluated trastuzumab plus radiotherapy in patients with HER2-positive, chemotherapy-refractory, locally advanced or locoregionally recurrent breast cancer. METHODS AND MATERIALS: Eligible patients had measurable disease, normal cardiac function, and biopsy-confirmed residual HER2-positive disease. Patients received weekly trastuzumab (2 mg/kg intravenously), concurrent with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks. If feasible, surgery followed radiotherapy. The primary endpoint was safety, and the secondary endpoint was efficacy (pathologic response and interval to symptomatic local progression). RESULTS: Of the 19 patients enrolled, 7 were ineligible and received radiotherapy alone and 12 received therapy per protocol. Of these 12 patients, 11 had a Stage T4 diagnosis. Grade 3 toxicities included skin (n = 2) and lymphopenia (n = 1). One patient experienced delayed wound healing after surgery. No patients developed symptomatic cardiac dysfunction. Of the 7 patients who had undergone mastectomy, 3 (43%) had a substantial pathologic response (complete response or microscopic residual disease), significantly more than a comparison cohort (2 of 38 or 5%, p = .02). The median interval to symptomatic local progression was not reached. The median overall survival was 39 months. CONCLUSION: This is the first prospective trial providing evidence for a radiosensitizing effect of trastuzumab in breast cancer. The combination of trastuzumab and radiotherapy was well tolerated.

Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK.

BACKGROUND AND PURPOSE: We recently showed that lapatinib, an EGFR/HER2 inhibitor, radiosensitized breast cancer cells of the basal and HER2+ subtypes. The purpose of this study was to identify the downstream signaling pathways responsible for lapatinib-mediated radiosensitization in breast cancer. MATERIALS AND METHODS: Response of EGFR downstream signaling pathways was assessed by Western blot and clonogenic cell survival assays in breast tumor cells after irradiation (5Gy), lapatinib, CI-1040, or combined treatment. RESULTS: In SUM102 cells, an EGFR+ basal breast cancer cell line, exposure to ionizing radiation elicited strong activation of ERK1/2 and JNK, which was blocked by lapatinib, and weak/no activation of p38, AKT or STAT3. Direct inhibition of MEK1 with CI-1040 resulted in 95% inhibition of surviving colonies when combined with radiation while inhibition of JNK with SP600125 had no effect. Lapatinib-mediated radiosensitization of SUM102 cells was completely abrogated with expression of constitutively active Raf. Treatment of lapatinib-resistant SUM185 cells with CI-1040 restored radiosensitization with 45% fewer surviving colonies when combined with radiation. CONCLUSIONS: These data suggest that radiosensitization by lapatinib is mediated largely through inhibition of MEK/ERK and that direct inhibition of this pathway may provide an additional avenue of radiosensitization in EGFR+ or HER2+ breast cancers.

EGFR associated expression profiles vary with breast tumor subtype.

BACKGROUND: The epidermal growth factor receptor (EGFR/HER1) and its downstream signaling events are important for regulating cell growth and behavior in many epithelial tumors types. In breast cancer, the role of EGFR is complex and appears to vary relative to important clinical features including estrogen receptor (ER) status. To investigate EGFR-signaling using a genomics approach, several breast basal-like and luminal epithelial cell lines were examined for sensitivity to EGFR inhibitors. An EGFR-associated gene expression signature was identified in the basal-like SUM102 cell line and was used to classify a diverse set of sporadic breast tumors. RESULTS: In vitro, breast basal-like cell lines were more sensitive to EGFR inhibitors compared to luminal cell lines. The basal-like tumor derived lines were also the most sensitive to carboplatin, which acted synergistically with cetuximab. An EGFR-associated signature was developed in vitro, evaluated on 241 primary breast tumors; three distinct clusters of genes were evident in vivo, two of which were predictive of poor patient outcomes. These EGFR-associated poor prognostic signatures were highly expressed in almost all basal-like tumors and many of the HER2+/ER- and Luminal B tumors. CONCLUSION: These results suggest that breast basal-like cell lines are sensitive to EGFR inhibitors and carboplatin, and this combination may also be synergistic. In vivo, the EGFR-signatures were of prognostic value, were associated with tumor subtype, and were uniquely associated with the high expression of distinct EGFR-RAS-MEK pathway genes.

The HER4 cytoplasmic domain, but not its C terminus, inhibits mammary cell proliferation.

Unlike the proliferative action of other epidermal growth factor (EGF) receptor family members, HER4/ErbB4 is often associated with growth-inhibitory and differentiation signaling. These actions may involve HER4 two-step proteolytic processing by intramembraneous gamma-secretase, releasing the soluble, intracellular 80-kDa HER4 cytoplasmic domain, s80HER4. We demonstrate that pharmacological inhibition of either gamma-secretase activity or HER4 tyrosine kinase activity blocked heregulin-dependent growth inhibition of SUM44 breast cancer cells. We next generated breast cell lines stably expressing GFP-s80HER4 [green fluorescent protein (GFP) fused to the N terminus of the HER4 cytoplasmic domain, residues 676-1308], GFP-CT(HER4) (GFP fused to N terminus of the HER4 C-terminus distal to the tyrosine kinase domain, residues 989-1308), or GFP alone. Both GFP-s80HER4 and GFP-CTHER4 were found in the nucleus, but GFP-s80HER4 accumulated to a greater extent and sustained its nuclear localization. s80HER4 was constitutively tyrosine phosphorylated, and treatment of cells with a specific HER family tyrosine kinase inhibitor 1) blocked tyrosine phosphorylation; 2) markedly diminished GFP-s80HER4 nuclear localization; and 3) reduced signal transducer and activator of transcription (STAT)5A tyrosine phosphorylation and nuclear localization as well as GFP-s80HER4:STAT5A interaction. Multiple normal mammary and breast cancer cell lines, stably expressing GFP-s80HER4 (SUM44, MDA-MB-453, MCF10A, SUM102, and HC11) were growth inhibited compared with the same cell line expressing GFP-CTHER4 or GFP alone. The s80HER4-induced cell number reduction was due to slower growth because rates of apoptosis were equivalent in GFP-, GFP-CTHER4-, and GFP-s80HER4-expressing cells. Lastly, GFP-s80HER4 enhanced differentiation signaling as indicated by increased basal and prolactin-dependent beta-casein expression. These results indicate that surface HER4 tyrosine phosphorylation and ligand-dependent release of s80HER4 are necessary, and s80HER4 signaling is sufficient for HER4-dependent growth inhibition.

The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes.

PURPOSE: Gene expression analysis identifies several breast cancer subtypes. We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes. EXPERIMENTAL DESIGN: We used immunohistochemical profiles [human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-negative for HER2+/estrogen receptor-negative (ER-), hormone receptor and HER2- for basal-like, hormone receptor-positive for luminal] to subtype a prospectively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based (doxorubicin plus cyclophosphamide, AC) chemotherapy. We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease-free survival and overall survival. RESULTS: Of the 107 patients tested, 34 (32%) were basal-like, 11 (10%) were HER2+/ER-, and 62 (58%) were luminal. After neoadjuvant AC, 75% received subsequent chemotherapy and all received endocrine therapy if hormone receptor-positive. The chemotherapy regimen and pretreatment stage did not differ by subtype. Clinical response to AC was higher among the HER2+/ER- (70%) and basal-like (85%) than the luminal subtypes (47%; P < 0.0001). Pathologic complete response occurred in 36% of HER2+/ER-, 27% of basal-like, and 7% of luminal subtypes (P = 0.01). Despite initial chemosensitivity, patients with the basal-like and HER2+/ER- subtypes had worse distant disease-free survival (P = 0.04) and overall survival (P = 0.02) than those with the luminal subtypes. Regardless of subtype, only 2 of 17 patients with pathologic complete response relapsed. The worse outcome among basal-like and HER+/ER- subtypes was due to higher relapse among those with residual disease (P = 0.003). CONCLUSIONS: Basal-like and HER2+/ER- subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers. Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype. The poorer prognosis of basal-like and HER2+/ER- breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved.

In vivo intraoperative radiotherapy: a novel approach to radiotherapy for early stage breast cancer.

INTRODUCTION: Intraoperative radiotherapy (IORT) has the potential to eliminate the access problems associated with standard 6-week post-operative external beam radiotherapy for patients with breast cancer. However, accurate delivery of the IORT dose for breast cancer has been problematic due to difficulty estimating the tumor bed after tumor removal and tissue re-approximation. We are investigating the feasibility of partial breast irradiation using a single fraction of IORT delivered to the tumor in vivo prior to surgical resection. METHODS: In a trial, approved by the University of North Carolina School of Medicine Institutional Review Board, patients > or =55 years old with infiltrating ductal carcinoma without an extensive intraductal component with an overall tumor size < or =3.0 cm receive a single dose of IORT in place of standard post-operative radiotherapy. RESULTS: All patients undergo preoperative ultrasonography to define the target volume. In a standard operating room, the tumor is exposed through a standard partial mastectomy incision. IORT is then delivered using a mobile, self-shielded, magnetron-driven X-band linear accelerator (Intraop Corp, Santa Clara, CA, USA). 15 Gy is delivered to the 90% isodose line covering the tumor with a 1 cm margin anterior-posterior and 2 cm margins laterally. After IORT, partial mastectomy is performed in the usual manner. CONCLUSIONS: IORT for breast cancer, delivered to the exposed tumor in vivo, is feasible and allows accurate estimation of the tumor bed. Further follow-up is ongoing to determine the efficacy of this approach.

Feasibility of breast preserving therapy with single fraction in situ radiotherapy delivered intraoperatively.

BACKGROUND: Accelerated partial breast irradiation (APBI) has gained widespread interest as a means of improving the convenience and availability of breast conserving radiotherapy. Intraoperative radiation therapy (IORT) is an APBI technique that delivers breast radiotherapy as a single dose at the time of partial mastectomy. We adapted the technique of Veronesi to deliver IORT prior to tumor excision to improve delivery to the region at risk and reduce the volume of normal tissue irradiated. METHODS: Patients age >or=55 with ultrasonographically defined tumors

Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.

The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells.

ERBB4/HER4 (referred to here as ERBB4) is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2/HER2/NEU, and ERBB3), which are associated with aggressive forms of human cancers, ERBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we show that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. We further show that ligand activation and subsequent proteolytic processing of endogenous ERBB4 results in mitochondrial accumulation of the ERBB4 intracellular domain (4ICD) and cytochrome c efflux, the essential and committed step of mitochondrial regulated apoptosis. Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK. Similar to other BH3-only proteins, 4ICD cell-killing activity requires an intact BH3 domain and 4ICD interaction with the antiapoptotic protein BCL-2, suppressed 4ICD-induced apoptosis. Unique among BH3-only proteins, however, is the essential requirement of BAK but not BAX to transmit the 4ICD apoptotic signal. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Thus, we propose that ligand-induced mitochondrial accumulation of 4ICD represents a unique mechanism of action for transmembrane receptors, directly coupling a cell surface signal to the tumor cell mitochondrial apoptotic pathway.

Axillary lymph node count is lower after neoadjuvant chemotherapy.

BACKGROUND: Retrieval of fewer than 10 lymph nodes at axillary dissection (ALND) for breast cancer can represent anatomic variation or inadequate dissection. We postulated that despite aggressive ALND, a lower lymph node count is more frequent after neoadjuvant chemotherapy. METHODS: Patients who received neoadjuvant chemotherapy followed by ALND were compared with patients who received surgery first. All patients received a level I and II ALND at a single institution by one of the breast surgeons. The number of nodes retrieved at ALND was dichotomized into categories (< 10 and > or = 10), and compared using Fisher exact test. RESULTS: A total of 143 neoadjuvant and 170 surgery-first patients were studied. Patients treated with neoadjuvant chemotherapy were significantly more likely to have fewer than 10 lymph nodes retrieved at ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%, P = .003). CONCLUSIONS: A low lymph node count is more common in patients after treatment with neoadjuvant chemotherapy and should not be assumed to represent an incomplete ALND.

Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic.

BACKGROUND: The prognostic significance of micrometastasis after neoadjuvant chemotherapy for locally advanced breast cancer is unknown. We examined the residual lymph node metastasis size in patients after treatment with neoadjuvant chemotherapy to determine the relevance of metastasis size on outcome. METHODS: Stage II/III breast cancer patients treated with neoadjuvant chemotherapy at our institution from 1991 to 2002 were included. We examined the relationship of postneoadjuvant chemotherapy lymph node metastasis size and number with distant disease-free survival (DDFS) and overall survival (OS). RESULTS: In 122 patients with a median follow-up of 5.4 years, we found not only that patients with an increasing number of residual positive nodes had progressively worse DDFS and OS (P < .0001 for both) compared with patients with negative nodes, but also that the size of the largest lymph node metastasis was associated with worse DDFS and OS (P < .0001 for both) in both univariate and multivariate analysis. Compared with negative nodes, even lymph node micrometastasis (<2 mm) was associated with worsened DDFS and OS (adjusted P = .02 and P = .005, respectively). CONCLUSIONS: Residual micrometastatic disease in the axillary lymph nodes after neoadjuvant chemotherapy is predictive of worse prognosis than negative nodes. In this study, the lymph node metastasis size and the number of involved lymph nodes were independent powerful predictors of DDFS and OS.

Postmastectomy radiotherapy in intermediate-risk patients: the gray zone.

Postmastectomy radiotherapy continues to be one of the most controversial issues in breast radiotherapy. At the crux of the controversy lies the lack of conclusive studies that specifically address the risk-benefit ratio of postmastectomy radiotherapy for patients at intermediate risk of developing locoregional recurrence. A well-designed phase III trial was initiated, but the trial failed to accrue and was closed prematurely, leaving the issue unresolved. Recent data confirm that postmastectomy radiotherapy yields a clear benefit in breast cancer-specific survival. Furthermore, the risk of cardiac morbidity that historically has offset the benefit of postmastectomy radiotherapy appears to be lessening with modern radiotherapy approaches. However, newer, more efficacious systemic therapy regimens may decrease the risk of locoregional recurrence and increase the risk of toxicity from combined-modality therapy. Recent studies attempt to better stratify patients into risk categories based on disease factors and to estimate the benefit of postmastectomy radiotherapy when traditional risk estimates, such as nodal status, are obscured by neoadjuvant systemic therapy. Nonetheless, a clear consensus on the role of postmastectomy radiotherapy remains elusive for patients who are at intermediate risk of locoregional recurrence after mastectomy.

Comparison of three concomitant boost techniques for early-stage breast cancer.

PURPOSE: Whole breast radiotherapy (RT) followed by a tumor bed boost typically spans 5-6 weeks of treatment. Interest is growing in RT regimens, such as concomitant boost, that decrease overall treatment time, lessening the time/cost burden to patients and facilities. METHODS AND MATERIALS: Computed tomography (CT) scans from 20 cases were selected for this retrospective, dosimetric study to compare three different techniques of concomitant boost delivery: (1) standard tangents plus an electron boost, (2) intensity-modulated RT (IMRT) tangents using custom compensators plus an electron boost, and (3) IMRT tangents plus a conformal photon boost. The equivalent uniform dose model was used to compare the plans. RESULTS: The average breast equivalent uniform dose value for the three techniques (standard, IMRT plus electrons, and IMRT plus photons) was 48.6, 47.9, and 48.3, respectively. The plans using IMRT more closely approximated the prescribed dose of 46 Gy to the whole breast. The breast volume receiving >110% of the dose was less with the IMRT tangents than with standard RT (p = 0.037), but no significant difference in the maximal dose or other evaluated parameters was noted. CONCLUSION: Although the IMRT techniques delivered the prescribed dose with better dose uniformity, the small improvement seen did not support a goal of improved resource use.