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-indottiBRCA mutationGravidanza e neoplasia mammaria

Incidenza

Fattori prognostici




Establishing the definition of “young” patients with 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 recurrencethe 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

Incidenza

Fattori prognostici





Age, tumor size, margins, systemic treatmentCefaro A.G, 2006

Age, EIC, marginsHorst KD, 2005

Age, marginsLeong C, 2004

Age, margins, chemotherapy, tamoxifeneLivi L, 2007

Age, ductal and ductal plus lobular histotypes, 3positive nodesLivi L, 2010

Regardless of the definition most series suggest a worse prognosis in young women compared with older women

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 cancersCarey LA, 2006Cancello G, 2010Bauer KR, 2007

young women tend to have tumors that are higher grade, have more extensive intraductal component, more lymphovascular space invasion, and are likely estrogen receptor (ER)-negativeNixon AJ, 1994Kutz JM, 1990Albain KS, 1994Leborgne 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 2008Perou 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 criteria cannot 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 youngwomen and concluded that this could define a unique

biologic entity.

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

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 yearsFredholm H, 2009

Worse outcome in local control and….

This negative impact on survival was especially seen in patients with positive lymph nodes and those withpositive 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, mortality in 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

Incidenza

Fattori prognostici





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 healthSteffi 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 bydigital 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

Incidenza

Fattori prognostici





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 most frequent definition of young age, patients ≤35 years old, there is evidence of higher rates of LRR when BCT is used as locoregional treatment

Using the most frequent definition of young age, patients ≤35 years old, there is evidence of higher rates of LRR when BCT is used as locoregional treatment.Oh JL, 2006Kim SH, 1998RechtA, 1988

10-year actuarial LRR rate ( <35 years old) 20%.Beadle, 200910-year actuarial LRR rate ( <35 years old) 28%.Elkhuizen, 199810-year actuarial LRR rate (29-39 years old) 18%Coulombe, 2007

Coulombe G, 2007Kroman N, 2004Veronesi U, 2002

From two Dutch regional population-based cancer registries 1,453 women <40 years pathologically T1N0–1M0 breast 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.

2011

ENJA J. BANTEMA-JOPPE, 2011

N -

N +

median follow-up of 9.6 years

83%

78%

84%

81%

79%

71%

the higher rates of LRR that have been shown make the choice of BCT or mastectomy especially controversial, but….

data from largely retrospective trials and the lack ofinformation regarding the use of postmastectomy radiation in the mastectomy cohort

historic datasets that may no longer be applicable in the time of modern surgery, radiation therapy chemotherapy

quality of life and body image

Beadle 2011

The radiation oncologist have to irradiate the whole breast, using CT-based radiotherapy assuring that the right target is hit, with as little normal tissue as possible in order to achieve an optimal therapeutic ratio.

Let’s make things better….

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, youth was the single,significant factor related to local recurrence

The previous report on the EORTC trial established that for patients 40 years old or less, an additional radiation boost (16 Gy to the tumor bed) reduced the 5-year local recurrence rate from 20% to 10%

19,3%

9,8%

Differenza 9,8%

Differenza 1.9%

The standard of care for adjuvant RT of early

breast carcinoma is whole breast irradiation

Young patients are unsuitable for APBI

Gec-ESTRO, 2010

ASTRO 2009

One of the continuing controversies in the treatmentof patients with BCT is the appropriate dose and fractionation of treatment.

Trattamento conservativo del carcinoma infiltrante nelle donne giovaniSi 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

Incidenza

Fattori prognostici





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 of 3729 women were eligible for analysis.

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

RT reduced the absolute 10-year risk of any ipsilateral breast event

The proportional reduction in 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 was 36.3 years and median 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 margins12%16%

Tunon de Lara, 2010

In patients with relapses, the 10-year survival rate was 67.2% compared to 98% overall for patients with no

recurrences.

The 10-year global breast-specific survival rates after M, LA or LRT were 98.4%, 98.2% and 94.7%

respectively.

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 2005Cutuli B, Presse Med 2004Bijker N, J Clin oncol 2006Fowble B, IJROBP 1997Fisher ER, Cancer 2004Omlin A, Lancet Oncol 2006

Tunon de Lara, 2010

Patients under 40 with DCIS constitute a particularlypoor prognosis group with a higher risk of recurrence and poorer survival.

Age appears to be one more parameter that shouldbe considered in the complex decision-making process ifwe want to reduce local recurrence risks, thus improvingchances for survival Tunon de Lara, 2010

We recommend to limit the use of a safe conservativesurgery

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 comedocarcinomaor 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 2006373 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 giovaniLa RT dopo chirurgia conservativa adeguata, secondo la maggior parte degli autori, riduce il rischio di ricaduta locale

Sempre secondo alcuni autori, il boost 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

Incidenza

Fattori prognostici





Forme avanzate, ad alto e medio rischio…

Post-mastectomy radiation therapy was strongly supported for patients with four or more axillary lymph nodes involved.

While not in general favoring irradiation for those with lesser nodal involvement, the Panel by a slim majority favored post-mastectomy radiation for patients younger than 45 years with 1–3 positive nodes andfor patients at any age with extensive vascular invasion in two or more blocks in conjunction with 1–3 positive nodes.

patient-related factors:

• age <40 years,• tumor 3 cm,• negative estrogen receptor• lymphovascular invasion.

66.7%

7.8%

p 0.0001

2002

In node negative patients, post-mastectomy RT should be indicated on the basis of the existence of one or more risk factors for local relapse, described by the working group as:

age less than 40 years, size ≥pT3,grade III,multifocality, lymphovascular and/or muscular and/or cutaneous invasion (expert agreement).

Whatever the type of surgery and the response to neoadjuvant CT………………………the RT indication should be taken into consideration by considering the initial tumour criteria. Belkacemy Y, Crit Rev Oncol Hematol 2010

Malattia localmente avanzata, inoperabile all'esordioChirurgia

Mc Guire SE, 2007

the LRR risk after neoadjuvant

chemotherapy and mastectomy is determined not just by

the extent of residual

disease after treatment but also by the extent of disease before treatment

Freedom from local recurrence

….radiation use was also associated with a statistically significant reduction in the rate of Distant Metatases and an improved CauseSpecificSurvival and Overal Survival in the

patients with Stage III disease.

Mc Guire SE

freedom from distant relapse Overall survival

è indicata la RT…

Dopo CT neoadiuvante

Trattamento delle forme avanzate, alto e medio rischio, anche in caso di mastectomia, insorte nelle donne giovani

La RT deve essere eseguita in caso di • T>5 cm, T4• N+ in numero > a 4 • N+ 13 … giovane età è un fattore di rischio • N0 con fattori di rischio… giovane età• dopo CT neoadiuvante per LABC, anche in caso

di ricostruzione

Problematiche da affrontare nelle pazienti giovani:


40% of all second tumors among women with breast cancer, with a 25-year cumulative risk of 6.9%.

largely related to preexisting breast cancer risk factors, but prior radiation therapy, especially treatment at a young age, may contribute to increased risk.

In early case-control studies the overall relative risk of contralateral breast cancer was not significantly increased after radiation therapy (RR 1.2; 95% CI, 0.94, 1.2).Boice JD Jr, N Engl J Med 1992Storm HH, Br J Cancer 1986

Controlateral breast cancer

ma…

among women age <45 years at the time of irradiation, the relative risk in the Boice et al study was 1.6Boice JD Jr, N Engl J Med 1992women 40 years of age who received 1 Gy of absorbed radiation dose to the contralateral breast had a 2.5-fold greater risk for cancer than unexposed women

for women 40 years of age followed for 5 years, a 3-fold risk was observed, with a significant dose–responseStovall M, IJROBP 2008

Other solid tumors that have been linked to RT for breast cancer include lung cancer, esophageal cancer, and soft tissue sarcoma…..

In several studies, women who received radiation had a 1.5- to 3-fold increased risk of developing lung cancer compared with women who did not receive radiation therapy.

Il miglior trattamento oggi…..

I rischi didomani…

La complicanza più grave che possiamo evidenziare….

è il mancato controllo della malattia

628 women age 40 and younger diagnosed with breastcancer from 1996 to 2008.

Tumors were first detected by self-examination in 71%, with a median invasive tumor size of 2.0 cm.

Imaging performed at or after diagnosis visualized most tumors;

mammography visualized 86%,magnetic resonance imaging (MRI) visualized

96%, mammography plus MRI visualized more than 98%

For 81% of patients, the mammogram at diagnosis was their first mammogram.

Although 50% had a family history of breast or ovarian cancer, few underwent genetic testing before their cancer diagnosis; 61 of 247 (25%) ultimately tested had a BRCA mutation

BRCA2 mutation carriers, on the contrary, present tumours with pathologic features similar to those of sporadic tumoursRobson M, 2004Venkitaraman A, 2002

BRCA1 mutation carriers develop tumours of a higher grade and proliferation index, with lower oestrogen receptor levels than patients with no such mutation, and tend to have worse outcomes Chappuis PO, 2000Adem C, 2003Stoppa-Lyonnet D, 2000Foulkes WD, 2000

Mastectomia o trattamento conservativo?

Ruolo della radioterapia in pazienti con mutazione BRCA: è efficace nel prevenire le ricadute?

Il trattamento locale influenza la sopravvivenza?

BRCA1 and BRCA2 mutation carriers show enhancedradiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms , with increased radiation-induced apoptosis.

Beroukas E, IJROBP 2010Gowen LC, 1998Hanawalt PC, 1994Freneaux p, 2000

The molecular pathway involved in DNA repair, particularly the role of BRCA1/2 proteins, would suggest a profile of tumor resistance to ionizing radiation in case of BRCA1/2 mutationBourgier C, 2010

morte cellulare programmataper danno al DNA dovuto a RT

Familial breast cancer: clinical response to inductionchemotherapy or radiotherapy related to BRCA1/2mutations status.Fourquet A, Am J Clin Oncol. 2009

90 pts (93 tumors)Median tumor size was 40 mm induction CT +/- RT

complete clinical response 15/39 (46%) BRCA 1/2 mutated 7/54 (17%) non mutated tumors (P = 0.008).

The overall complete or major clinical response rate in the tumors treated with induction radiotherapy was 68% (13/19 tumors).

Breast conservation after induction treatment was higher in BRmut+ tumors, and clinical response was related to aggressive tumor features correlated with BRCA1/2 mutations.

This suggests that impaired repair mechanisms related to the BRCA1/2 mutations increased the chemosensitivity and radiosensitivity of large breast cancers

Forquet A, 2009

ma…

An incorrect repair of DNA double-strand breaks after IR, due to BRCA1/2 mutation, could lead to the development of new primary breast cancer

As the residual presence of breast tissue which still contains all remaining cells carrying the same deleterious mutations

Bourgier C, 2010

655 breast cancer with BRCA1/2 mutations

BCT (n = 302) LR 23.5% (p=0,0001)M (n = 353) LR 5.5%

BCT + chemotherapy was 11.9% (P = 0.08 compared to M)

2010

Local failure

Cons. Treatm

Mastect.

Pierce L, 2010

23.5%

5.5%

70% second tumors

82% true recur.

RT

RT+CT

Chirurgia conservativa

>chemiosensibilitàFourquet A, 2009

Pierce L, 2010at 15 years

Aumento delle neoplasie controlaterali

Metcalfe, JCO 2004BRCA1 43%BRCA2 35% a 10 aa

Pierce L, JCO 2006BRCA1/2 45%

Although studies have shown a risk reduction ofCBC in BRCA mutation carriers who take tamoxifen orundergo oophorectomy, no intervention has shown more efficacy in reducing this risk than contralateral prophylactic mastectomy, which can decrease it by up to 91%

5% in Europe 28% in Canada 49% in the United States.

It is not clear whether this difference was a result ofpatient preference or because the operation was not routinely offered in European countries.

there is proven efficacy of prophylactic mastectomy for risk reduction, there are no data to support an improvement in survival compared with close surveillance.

Prophylactic mastectomy in BRCA mutated patients

Pazienti sottoposte ad attenta sorveglianza e valutazione clinico strumentale Possibilità di diagnosi precoce

Aumento delle ricadute locali dopo chirurgia conservativa, malgrado la maggiore sensibilità a RT e CT

Sembrano essere prevalentemente seconde neoplasie e non ricadute vere

IEO

Aumento delle neoplasie controlaterali, per le quali la terapia più efficace sembra essere la mastectomia profilattica.

Non si evidenzia aumento delle ricadute regionali o sistemiche legate al tipo di trattamento locale

Non ci sono dati che dimostrino per altro che un trattamento chirurgico radicale ottenga migliori risultati in sopravvivenza della stretta e accurata sorveglianza

neoplasia mammaria e mutazione BRCA…..

Trattemento conservativo ?

Mastectomia ?

Coinvolgimento psicologico………gestire il rischio di avere di nuovo una neoplasia otollerare lo stress legato ad una mutilazione, sia pur con ricostruzione?

La decisione deve essere presa con la paziente dopo adeguata informazione sui rischi e sui benefici delle diverse opzioni terapeutiche

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Problematiche da affrontare nelle pazienti giovani:

Gravidanza e neoplasia mammaria

Carcinoma mammario insorto durante gravidanza

Gravidanza in paziente trattatain precedenza per neoplasia mammaria

evento raro, di psicologico profondo impatto sulla vita della paziente, della sua famiglia e del medico e che comporta anche risvolti di tipo etico e confessionale.

Per le tossicità attese dai diversi trattamenti, non è sempre possibile ottenere il massimo beneficio per lapaziente ed il minimo danno per il feto ed è necessaria una precisa conoscenza dei dati della letteratura e dei fenomeni biologici coinvolti

La decisione della paziente va sempre rispettata

Carcinoma mammario insorto durantela gravidanza…

Time after conception (weeks)

EffectDose threshold

0–2 Prenatal death 10 cGydeterministic

2-15Malformation, Microcephaly, growth retardation

10-20 cGy

8–25Mental retardation, IQ decrease, Growth retardation

10 cGy50 cGy

0–38

Leukaemia, solid tumours in childhood, lifetime risk of fatal cancer after fetal exposure, hereditary effects through generations

stochastic

Sebbene non vi sia unanime consenso e alcuni autori presentino dati su bambini nati sani dopo irradiazione con dosi significative (0,039 Gy al primo trimestre; 0,14-0,18 Gy al terzo trimestre), la maggior parte delle fonti bibliografiche considera

la gravidanza, in ogni epoca gestazionale,

una controindicazione assoluta al trattamento radiante

Diagnosi nel primo trimestre: Mastectomia + DA, eventuale PMRT dopo il parto

Diagnosi alla fine del secondo o nel terzo trimestre:

chirurgia conservativa seguita da RT da effettuarsi dopo il parto, (eventualmente anticipato non appena vi siano idonee condizioni di maturazione respiratoria per il bambino).

La possibile disfunzione ovarica indotta dalla chemioterapia adiuvante può rendere difficoltoso il realizzarsi di una gravidanza .

Solo il 10% delle donne trattate per neoplasia mammaria concepisce e complessivamente si riscontra in questa popolazione la metà delle maternità registrate nella popolazione sana di analoga età

Oktem O, Cancer 2007Ives A, BMJ 2007

Gravidanza in paziente trattata in precedenza per neoplasia mammaria

La gravidanza non sembra influenzare negativamente la prognosi.

Generalmente si consiglia di dilazionare il concepimento fino ad almeno due anni dal termine dei trattamenti: non è noto quale sia il tempo ottimale, ma si considera che il maggior rischio di ricaduta si riscontri entro tale limite.

L’allattamento, che può essere reso problematico dalla precedente radioterapia, non aumenta il rischio di ripresa di malattia o di una eventuale comparsa di neoplasia nel bambino allattato.

Hickey M, 2009Ives A 2007

Incidenza

Fattori prognostici





Treatment of very young women

Marina Guenzi Oncolgia Radioterapica Genova

Treatment of very young women Marina Guenzi Oncolgia Radioterapica Genova.

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Transcript of Treatment of very young women Marina Guenzi Oncolgia Radioterapica Genova.