Treatment of very young women Marina Guenzi Oncolgia Radioterapica Genova

Treatment of very young women Marina Guenzi Oncolgia Radioterapica Genova

Incidenza Fattori prognostici Procedure Diagnostiche Il trattamento locale nel carcinoma infiltrante Il trattamento locale nel carcinoma in situ Trattamento delle forme avanzate, alto e medio rischio

problematiche da affrontare nelle pazienti giovani: Secondi Tumori Radio-indotti BRCA mutation Gravidanza e neoplasia mammaria

Incidenza Fattori prognostici Il trattamento locale nel carcinoma infiltrante Il trattamento locale nel carcinoma in situ Trattamento delle forme avanzate, alto e medio rischio

Establishing the definition of “young” patientswith breast cancer has been the subject of some controversy women “35 to 40 years of age or younger” defined a group of patients in which age was an independent risk factor for higher rates of recurrence the MEDLINE and CancerLit databases most series recognize patients ≤35 years old as a “young” population. Beadle et al., 2011

Breast cancer in women ≤40 years of age is relatively uncommon, reflecting only 5% of new breast cancers from 2002 to 2006. Breast cancer is rare in very young women. Only 1.9% of all breast cancers occur in women 35 years, but the diagnosis is physically and emotionally devastating for these women Further data indicate that women aged 20 to 24 had the lowest breast cancer incidence rate, with 1.4 cases per 100,000 women. American Cancer Society,2010

2010

Regardless of the definition most series suggest a worse prognosis in young women compared with older women Age, tumor size, margins, systemic treatment Cefaro A.G, 2006 Age, EIC, margins Horst KD, 2005 Age, margins Leong C, 2004 Age, margins, chemotherapy, tamoxifene Livi L, 2007 Age, ductal and ductal plus lobular histotypes, 3 positive nodes Livi L, 2010

The reasons for these higher rates of recurrence are unclear…. young women tend to have more triple-negative and fewer luminal A and B breast cancers Carey LA, 2006 Cancello G, 2010 Bauer KR, 2007 young women tend to havetumors that are higher grade, have more extensive intraductal component, more lymphovascular space invasion, and are likely estrogen receptor (ER)-negative Nixon AJ, 1994 Kutz JM, 1990 Albain KS, 1994 Leborgne F, 1994

Breast tumors arising in younger women may be more enriched for aggressive subtypes and age-specific biologic differences observed in breast carcinomas may be highly subtype dependent. Anders CK, JCO 2008 Perou CM, Nature 2000

However, even after adjustment of those prognostic factors, women aged 35 or younger still have a worse prognosis. Therefore, the unfavorable common prognostic criteriacannot be the only explanation for the more aggressive disease. Different gene expression profiles could explain the differences between the young and the elderly. Anders et al revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women and concluded that this could define a unique biologic entity.

Worse outcome in local control and…. the risk of dying of breast cancer within 5 years of diagnosis in women aged younger than 35 with Stage I–IIb breast cancer has been reported to be 1.8-fold higher than in women aged 50 to 69 years Fredholm H, 2009 this age group showed a significantly worse outcome compared with older premenopausal women, and their risk of death rose by 5% for every 1-year reduction in age. Han W, Breast Cancer Res Treat 2009

This negative impact on survival was especially seen in patients with positive lymph nodes and those with positive hormonal receptors, underlining the key role of hormonal mechanisms in young patients with breast cancer. El Shagir NS, BMC Cancer 2006

It should be noted that in spite of the still poorer prognosis compared with older women, mortalityin the younger age group decreased between 2000 and 2004 by around 30% (10 years follow up). This effect can partly be explained by the fact that younger patients are highly motivated and often have access to innovative therapeutic strategies, especially in clinical trials. Katalinic A, Breast Care 2009

Young women have a higher density of the glandular parenchyma, making it more difficult to differentiate between tumors and normal breast tissue by mammography. Sonography is more sensitive than mammography in evaluating breast masses in women younger than 45 making it more difficult to differentiate between tumors and normal breast tissue by mammography. Preoperative MRI did not reduce the reoperation rate may not be necessary and can result in extra use of resources with little or no benefit to residual health Steffi Hartmann, Clinical Breast Cancer 2011

In symptomatic young women, breast ultrasound should be the diagnostic method of choice and in case of a suspicious finding it should be supplemented by digital mammography and histologic assessment. In case of conventional imaging difficulties because of dense tissue, preoperative MRI may provide benefit in very young patients with breast cancer Steffi Hartmann, Clinical Breast Cancer 2011

Surgical management is not different from that in older patients. The decision about breast-conservation versus mastectomy is influenced by the fact that young women frequently present at an advanced stage Using the mostfrequentdefinition of youngage, patients ≤35 yearsold, thereisevidence of higherrates of LRR when BCT isusedaslocoregional treatment

Breastconserving treatment or mastectomy? Using the mostfrequentdefinition of youngage, patients ≤35 yearsold, thereisevidence of higherrates of LRR when BCT isusedaslocoregional treatment. Oh JL, 2006 Kim SH, 1998 RechtA, 1988 10-year actuarial LRR rate ( <35 years old) 20%. Beadle, 2009 10-year actuarial LRR rate ( <35 years old)  28%. Elkhuizen, 1998 10-year actuarial LRR rate (29-39 years old) 18% Coulombe, 2007

However, there is still controversy as to whether this difference in local control translates into inferior survival after BCT in young breast cancer patients Coulombe G, 2007 Kroman N, 2004 Veronesi U, 2002

2011 From two Dutch regional population-based cancer registries 1,453 women <40 years pathologically T1N0–1M0breast cancer were selected. Cox regression survival analysis was used to study the effect of local treatment (BCT vs. mastectomy) stratified for nodal stage on survival and corrected for tumor size, age, period of diagnosis, and use of adjuvant systemic therapy.

83% 84% 81% 78% N - 79% 71% N + median follow-up of 9.6 years ENJA J. BANTEMA-JOPPE, 2011

Breastconserving treatment or mastectomy? the higherrates of LRR thathavebeenshownmakethe choice of BCT or mastectomyespeciallycontroversial, but…. data from largelyretrospective trials and the lack of information regarding the use of postmastectomy radiation in the mastectomy cohort historicdatasetsthatmay no longer be applicable in the time of modernsurgery, radiationtherapychemotherapy quality of life and body image Beadle 2011

Breastconserving treatment or mastectomy? Is RT able to control microscopic foci?

Let’s make things better…. The radiation oncologist have to irradiate the whole breast, using CT-basedradiotherapyassuringthat the right target is hit, with as little normal tissue as possible in order to achieve an optimal therapeutic ratio.

A boost should be systematically administered, with dose homogeneity and no geographical miss. Improving the definition of the tumor-bed volume is of major importance to potentially decrease the relapse rate after breast-conserving surgery

In the EORTC 22881/10882 trial, youthwas the single, significantfactorrelated to localrecurrence The previous report on the EORTC trial establishedthat for patients40 yearsold or less, an additionalradiationboost (16 Gy to the tumor bed) reduced the 5-year localrecurrence rate from 20% to 10%

Differenza 9,8% 19,3% 9,8% Differenza 1.9%

The standard of care for adjuvant RT of earlybreast carcinoma iswholebreastirradiation Young patients are unsuitable for APBI

ASTRO 2009 Gec-ESTRO, 2010

One of the continuingcontroversies in the treatment of patients with BCT is the appropriate dose and fractionation of treatment.

Trattamento conservativo del carcinoma infiltrante nelle donne giovani Si considera indicata l’irradiazione dell’intero seno, dopo adeguata chirurgia conservativa (margini negativi ), con boost sul letto tumorale, correttamente identificato con l’ausilio di clip posizionate dal chirurgo Non sono disponibili dati “specifici” sull’irradiazione ipofrazionata Le pazienti giovani NON sono candidate a PBI

2010 Individual patient data were available for all four of the randomized trials that began before 1995, and that compared adjuvant radiotherapy vs no radiotherapy following breast-conserving surgery for ductal carcinoma in situ A total of 3925 women were randomized and a total of3729 women were eligible for analysis.

RT reduced the absolute 10-year risk of any ipsilateral breast event regardless of the age at diagnosis, extent of breast-conserving surgery, use of tamoxifen, method of DCIS detection, margin status, focality, grade, comedonecrosis, architecture, or tumor size

The proportional reductionin the rate of ipsilateral breast events achieved with radiotherapy was greater in older than in younger women but did not differ significantly according to any other factor.

From 1974 to 2003, 207 cases were collected in 12 French Cancer Centers. Median age was36.3 years andmedian follow-up 160 months. This study is the largest series of patients with DCIS aged under 40 published in the literature.

DCIS of the breast is a relatively rare disease in women under 40 years of age (approximately 4% of a total 7000 breast cancers per year in France), which tends to be diagnosed by clinical findings, incidentally, or after plastic surgery … women under 50 who are not part of French national screening programs and are diagnosed with more advanced tumor stages at diagnosis, greater analysis of predictive factors for recurrence is needed

Tunon de Lara, 2010

The 10-year actuarial recurrence rates were 3.3% (M), 23% (LA), 35.6% (LRT) 29.9% (LRT and boost). RT does not compensate for surgical margins which are not free of cancer In the EORTC trial, RT reduced the risk of local recurrences, but this decrease was less important in young patients than in older patients This rate of recurrences is similar to rates reported in the EORTC trial for younger women (34% at 10 years ) positive margins 12% 16% Tunon de Lara, 2010

The 10-year global breast-specific survival rates after M, LA or LRT were 98.4%, 98.2% and 94.7% respectively. In patients with relapses, the 10-year survival rate was 67.2% compared to 98% overall for patients with no recurrences. Tunon de Lara, 2010

The following were significant independent predictive factors of local recurrence: comedocarcinoma ( p 0.004), histological size >10 mm ( p 0.011), necrosis ( p 0.022) positive margins ( p 0.019) The following factors were not predictive of local recurrence: age under 35 ( p 0.32), tumor grade ( p 0.19) radiotherapy with (p 0.62) or without boost (p 0.33) Tunon de Lara, 2010

Impact of radiotherapy Unlike in other series radiation therapy with or without boost did not reduce the incidence of local recurrences. Solin LJ, Cancer 2005 Cutuli B, Presse Med 2004 Bijker N, J Clin oncol 2006 Fowble B, IJROBP 1997 Fisher ER, Cancer 2004 Omlin A, Lancet Oncol 2006 Tunon de Lara, 2010

Patients under 40 with DCIS constitute a particularly poor prognosis group with a higher risk of recurrence and poorer survival. Age appears to be one more parameter that should be considered in the complex decision-making process if we want to reduce local recurrence risks, thus improving chances for survival Tunon de Lara, 2010

We recommend to limit the use of a safe conservative surgery to tumors with margins 2 mm, DCIS size 11 mm or smaller free of necrosis and comedocarcinoma. Mastectomy ought to be proposed in cases of multifocal DCIS, tumors larger than 10 mm, positive margins after re-excision, DCIS with necrosis or comedocarcinoma or small breasts Tunon de Lara, 2010

Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network. Omlin A, Amichetti M, Azria D, et al. Lancet Oncol 2006 373 patients age 45 years or younger 10-year local-recurrence-free survival rates excision alone (15%), 46% excision + WBRT (45%) 72% excision WBRT + boost (40%); 86% (p<0·0001). The investigators conclude that a boost is useful in the management of DCIS.

Trattamento conservativo del carcinoma in situ nelle donne giovani La RT dopo chirurgia conservativaadeguata, secondo la maggior parte degli autori, riduce il rischio di ricaduta locale Sempre secondo alcuni autori, ilboost deve essere preso in considerazione, in base al rischio di ricaduta locale La mastectomia deve essere considerata, discussa con la paziente e proposta nei casi in cui la situazione sia tale da non consentire un adeguato controllo con la sola chirurgia conservativa

Treatment of very young women Marina Guenzi Oncolgia Radioterapica Genova